Palladium-Catalyzed One-Pot Stereospecific Synthesis of 2-Deoxy Aryl C-Glycosides from Glycals and Anilines in the Presence of tert-Butyl Nitrite

Article abstract of DOI:10.1055/s-0037-1611916

The palladium-catalyzed one-pot synthesis of 2,3-deoxy-3-keto aryl C-glycosides is achieved from glycals and anilines in the presence of tert-butyl nitrite and aqueous HBF ₄ under mild conditions. This one-pot method stereospecifically provides α-and β-Aryl glycosides (≥19:1 by NMR) in good yields at room temperature. The configuration at the C-3 position in the glycal determines the anomeric selectivity (i.e., α or β) of the desired products.

Full text of DOI:10.1055/s-0037-1611916

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–P
paper
A
en
A. K. Singh et al.
Paper
Synthesis
Palladium-Catalyzed One-Pot Stereospecific Synthesis of 2-Deoxy
Aryl C-Glycosides from Glycals and Anilines in the Presence of tert-
Butyl Nitrite
OR2
OR2
Adesh Kumar Singh
Rapelly Venkatesh
O
O
R1
R1
OR2
OR2
Jeyakumar Kandasamy*
0
0
0
0-
0
0
0
3-3
2
8
5-9
7
1
X
NH2
R2O
R2O
O
O
Department of Chemistry, Indian Institute of Technology
(BHU), Varanasi, Uttar Pradesh, 221005, India
jeyakumar.chy@iitbhu.ac.in
OR2
OR2
R1
t-BuONO, aq HBF4
R2O
R2O
Pd(OAc)2
CH3CN/H2O
Pd(OAc)2
CH3CN/H2O
dr: ≥ 19:1
(by NMR)
dr: ≥ 19:1
(by NMR)
O
O
R1 = Alkyl, Aryl, Halogen, NO2, etc.
R2 = Methyl (or) Benzyl
5 examples
55–68%
>25 examples
48–76%
Received: 22.06.2019
Accepted after revision: 08.08.2019
Published online: 26.08.2019
temperature in the absence of any ligand.6 In this context,
the Correia and Schmidt research groups independently ex-
plored the palladium-catalyzed arylations of different cyclic
enol ethers using aryldiazonium salts.6c–n
DOI: 10.1055/s-0037-1611916; Art ID: ss-2019-n0165-op
Abstract The palladium-catalyzed one-pot synthesis of 2,3-deoxy-3-
keto aryl C-glycosides is achieved from glycals and anilines in the pres-
ence of tert-butyl nitrite and aqueous HBF4 under mild conditions. This
one-pot method stereospecifically provides - and -aryl glycosides
(≥19:1 by NMR) in good yields at room temperature. The configuration
at the C-3 position in the glycal determines the anomeric selectivity
(i.e.,  or ) of the desired products.
O
O
O
HO
O
O
OH
O
O
HO
O
O
OH
Saquayamycin A
O
O
O
Key words palladium, C-glycosylation, aryldiazonium salts, stereospe-
cific, tert-butyl nitrite, anilines
O
O
Aryl C-glycosides are an important class of compounds
that display various biological activities.1 Among the differ-
ent types, 2-deoxy aryl C-glycoside motifs are found in var-
ious bioactive molecules and natural products.1 For in-
stance, natural products such as the pluramycins, angucy-
clines and benzoisochromanequinones consist of 2-deoxy
aryl C-glycoside units (Figure 1).2 There are a few different
routes that have been developed for the preparation of 2-
deoxy aryl glycosides.1,3,4 Among them, the direct coupling
of aryl donors such as aryl halides, arylboronic acids, aryl-
hydrazines, aryl carboxylic acids, arylsulfonyl halides, etc.
with glycals has received considerable attention in carbo-
hydrate synthesis.4 Notably, all these methods provide 2-
deoxy -aryl C-glycosides, while most of the naturally oc-
curring aryl C-glycosides exist with -configuration at the
anomeric center.
HO
O
OH
O
O
O
O
O
H
O
O
HO
H
(H3C)2N
O
OH
O
H
O
HO
N(CH3)2
N(CH3)2
OH
Pluramycin A
Medermycin
Figure 1 Natural products containing 2-deoxy aryl C-glycosides
Recently, we demonstrated a stereocontrolled synthesis
of 2,3-deoxy 3-keto -aryl C-glycosides from glycals and
aryldiazonium salts in the presence of palladium acetate at
room temperature.7 In addition, Ye et al. reported a palladi-
um-catalyzed one-pot synthesis of 2-deoxy aryl C-glyco-
sides from glycals and anilines using nitrosonium tetrafluo-
roborate as the nitrosating reagent.8 The important advan-
tage of this one-pot method is that isolation of the unstable
aryldiazonium salt intermediate is not required. However,
the use of nitrosonium tetrafluoroborate (NOBF4) as a nitro-
Aryldiazonium salts are highly useful synthetic inter-
mediates that have been explored in many organic reac-
tions.5 In particular, palladium-catalyzed Heck couplings of
allyl alcohols, allyl ethers and vinyl ethers with aryldiazoni-
um salts have received considerable attention in the past
few decades because such reactions take place at room
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. K. Singh et al.
Paper
Synthesis
OR2
OR2
O
O
R1
R1
OR2
OR2
NH2
R2O
R2O
O
O
O
OR2
OR2
R1
t-BuONO, aq HBF4
R2O
Pd(OAc)2
CH3CN/H2O
Pd(OAc)2
CH3CN/H2O
R2O
O
dr: ≥ 19:1
(by NMR)
dr: ≥ 19:1
(by NMR)
Scheme 1 Palladium-catalyzed stereoselective synthesis of 2-deoxy aryl C-glycosides
sating agent has some disadvantages. For instance, NOBF4 is
an expensive reagent and is highly reactive, which necessi-
tates a low temperature (i.e., –40 °C) and moisture-free
conditions for the diazotization process.8 Therefore, we be-
lieve that the development of an alternative one-pot proce-
dure using an inexpensive, stable and easily accessible ni-
trosating agent would provide a simple access to 2-deoxy
aryl C-glycosides from glycals and anilines under mild con-
ditions.
tert-Butyl nitrite (TBN) is an efficient nitrosating re-
agent that has been explored in many organic transforma-
tions.9 The diazotization of anilines has been successfully
achieved using tert-butyl nitrite under mild conditions.10
Moreover, TBN-mediated diazotizations followed by cross-
coupling reactions have also been successfully demonstrat-
ed in organic synthesis.9c,d Other advantages of TBN are its
low cost and commercially availability, and the fact that it is
economic and easy to store and handle. We have recently
demonstrated different applications of tert-butyl nitrite in
organic synthesis, including N-nitrosation of secondary
amines,11 oxidative dimerization of thioamides,12 conver-
sion of o-phenylenediamines into triazoles,13 nitration of N-
alkyl anilines14 and one-pot transamidation of secondary
amides.15 In continuation of this work, we herein report the
palladium-catalyzed one-pot synthesis of 2,3-deoxy 3-keto
aryl C-glycosides from glycals and anilines in the presence
of tert-butyl nitrite under mild conditions (Scheme 1).
Table 1 Optimization of the Reaction Conditionsa
MeO
NH2
(2a)
OMe
OMe
OBn
OBn
t-BuONO (2.0 equiv)
Additive (2.0 equiv)
CH3CN/H2O
OBn
O
O
O
BnO
BnO
+
BnO
~5 °C to RT, 30 min
O
O
OBn
[Pd] ( 10 mol%), RT, 4 h
3aa
3fb
dr > 99:1 (HPLC)
Entry
Additive
Catalyst
Yield of 3aa (%)b
1
2
HBF4 (aq 48%)
BF3·OEt2 (48%)
HPF6 (aq 55%)
CSA·H2O
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
76
56
72
10
7
3
4
5
PTSA·H2O
6
AcOH
5
7
HCl (aq 31%)
HBF4 (aq 48%)
HBF4 (aq 48%)
HBF4 (aq 48%)
HBF4 (aq 48%)
HBF4 (aq 48%)
<5
55
70
67
69
52
8
9
Pd(TFA)2
Pd(dba)2
Pd2(dba)3
Pd(PPh3)4
10
11
12
a Reaction conditions: glucal 1a (52 mg, 0.125 mmol) and the catalyst (0.012 mmol, 10 mol%) were added to a solution of the aryldiazonium compound generat-
ed in situ from aniline 2a (30 mg, 0.25 mmol, 2.0 equiv) and tert-butyl nitrite (0.029 mL, 0.25 mmol, 2.0 equiv) in the appropriate solvent (4 mL).
b Yield of isolated product.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

C
A. K. Singh et al.
Paper
Synthesis
At the outset, optimization of the reaction conditions
was performed using tri-O-benzyl glucal (1a) and 4-me-
thoxyaniline (2a) in the presence of TBN and Pd(OAc)2. Ini-
tially, 4-methoxyaniline was treated with 2 equivalents of
TBN at ~5 °C (in an ice bath) in different solvents including
acetonitrile/water, THF and methanol, and then subjected
to the coupling reaction with glucal 1a in the presence of 10
mol% of Pd(OAc)2 or Pd(dba)2 at room temperature (Table 1)
(see also the Supporting Information). However, the desired
coupling product was not obtained. Hence, the reaction was
performed using different acid additives including HBF4,
BF3·OEt2, HPF6, CSA, PTSA, AcOH and HCl in acetonitrile/wa-
ter mixture (Table 1, entries 1–7). To our delight, the de-
sired coupling product 3aa was obtained as a single isomer
(i.e., the -anomer) with most of these acid additives.
Among these additives, HBF4 was found to be the most effi-
cient and provided the desired product in 76% yield (dr >
99:1) (Table 1, entry 1). It is also interesting to note that the
corresponding -anomer 3fb was not observed by TLC or
HPLC analysis (see the Supporting Information). It is note-
worthy that Mabit et al. recently demonstrated a palladi-
um-catalyzed stereospecific synthesis of - and -aryl 2-
deoxy glycosides from glycals and haloarenes.4i In their re-
port, the authors showed that the stereochemistry at the
pseudo-anomeric position was controlled by the stereocen-
ter at the C-3 position in glycals. In fact, a similar mechanis-
tic aspect has been previously proposed by Schmidt et al. in
the preparation of diarylheptanoids using diazonium salts.6j
Further, the reaction was optimized with different sol-
vents in the presence of HBF4 (Table 1) (see also the Sup-
porting Information). Among them, acetonitrile/water mix-
ture proved to be the best solvent for the coupling reaction.
Under all these conditions, only the -isomer 3aa was ob-
tained, while the -anomer 3fb was not detected by TLC.
Further, different palladium catalysts including PdCl2,
Pd(TFA)2, Pd(dba)2, Pd2(dba)3 and Pd(PPh3)4 were screened
in the presence of TBN and HBF4 (Table 1, entries 8–12). The
catalysts Pd(TFA)2, Pd(dba)2 and Pd2(dba)3 showed similar
reactivity to that of palladium acetate in the coupling reac-
tion. Furthermore, optimization of the reaction conditions
was investigated with different metal and non-metal cata-
Table 2 Reactions of Protected Glucals with Different Anilinesa
NH2
OR1
OR1
R2
R2
O
O
O
t-BuONO, HBF4 48% (aq.)
CH3CN/H2O, ~5 °C to RT, 30 min
R1O
R1O
OR1
R1 = Bn = 1a
1 = Me = 1b
Pd(OAc)2 (10 mol%)
dr: ≥ 19:1
(by NMR)
R
Entry
R1
Bn
R2 (2)
Time (h)
Product Yield (%)b
1
2
H (2b)
5.5
4.0
3.5
4.0
4.0
4.5
6.0
5.5
4.0
5.5
3.5
6.0
3.5
4.0
4.5
3.5
5.5
3ab
3ac
3ad
3ae
3af
60
79
75
65
72
63
60
64
61
61
70
59
65
65
72
76
64
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
4-Me (2c)
4-Br (2d)
4-Cl ( 2e)
4-F (2f)
3
4
5
6
4-Ac (2g)
4-CN (2h)
4-COOMe (2i)
4-F3C (2j)
4-O2N (2k)
3-Cl (2l)
3ag
3ah
3ai
7
8
9
3aj
10
11
12
13
14
15
16
17
3ak
3al
3-O2N (2m)
2-Cl (2n)
2,4-Me (2o)
H (2b)
3am
3an
3ao
3ba
3bb
3bc
4-MeO (2a)
4-O2N (2k)
a Reaction conditions: see the general procedure.
b Yield of isolated product.
lysts (those known for the activation of aryldiazonium
salts), including CuI, CuCl, CuBr2, CuOAc, Cu(OAc)2, NiCl2,
ascorbic acid and tetrathiafulvalene (Scheme 2).5 Unfortu-
nately, none of these catalysts yielded the desired product.
NH2
R
OBn
OBn
t-BuONO, HBF4 (aq)
CH3CN/H2O, ~5 °C to RT, 30 min
R
O
O
O
MeO
t-BuONO (2 equiv)
NH2
BnO
BnO
OMe
Pd(OAc)2 (10 mol%)
dr: ≥ 19:1
(by NMR)
OBn
OBn
OBn
1c
O
HBF4, CH3CN/H2O
O
O
OMe
Cl
OBn
OBn
OBn
~ 5 °C to RT, 30 min
3aa
BnO
O
O
O
O
BnO
OBn
1a
Catalyst (10 mol%), RT, 4 h
BnO
BnO
BnO
3cc (6.5 h, 48%)
O
O
Catalyst:
CuI, CuCl, CuBr2, CuOAc, Cu(OAc)2, NiCl2, ascorbic acid, tetrathiafulvalene (TTF)
3ca (8 h, 48%)
3cb (6 h, 52%)
Scheme 3 Reactions of tri-O-benzyl galactal (1c) with different ani-
lines. See the general procedure for the reaction conditions
Scheme 2 Arylation of tri-O-benzyl glucal (1a) with 4-methoxyaniline
(2a) with different metal and non-metal catalysts
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

D
A. K. Singh et al.
Paper
Synthesis
I
OAc
OTs
O
NH2
O
O
1) K2CO3, MeOH, quant.
2) TsCl, Py, CH2Cl2
R
1) KI, TBAI, DMF
AcO
60 °C, 12 h
96%
O
t-BuONO, HBF4 (aq)
CH3CN/H2O, ~5 °C to RT, 30 min
AcO
R
AcO
O
O
OAc
3) Ac2O, Py, DMAP
65% (over two steps)
OAc
OAc
2
BnO
OBn
1d
1
dr: ≥ 19:1
(by NMR)
BnO
Pd(OAc)2 (10 mol%)
O
O
1) NaOMe, MeOH
3 h, quant.
Bu3SnH, AIBN
OMe
NO2
Toluene, 100 °C
3 h, 98%
2) NaH, BnBr, DMF
83%
AcO
BnO
O
O
O
O
NO2
OAc
OBn
1e
BnO
3
BnO
BnO
O
O
Scheme 5 Synthesis of di-O-benzylD-rhamnal from tri-O-acetyl glucal
3da (6 h, 67%)
3db (6 h, 65%)
3dc (5.5 h, 68%)
Scheme 4 Reactions of di-O-benzyl L-rhamnal (1d) with different ani-
lines. See the general procedure for the reaction conditions
NH2
With optimized conditions in hand, different function-
alized anilines were subjected to the diazotization followed
by the coupling reaction with protected glucals in the pres-
ence of TBN, aqueous HBF4 and palladium acetate (Table 2).
Alkyl-, halo-, cyano-, nitro- and carbonyl-functionalized
anilines underwent coupling reactions with perbenzylated
and permethylated glucals 1a and 1b to provide the desired
products 3ab–bc as single diastereomers () in 59–79%
yields (Table 2, entries 1–17). It is noteworthy that sterically
hindered ortho-substituted anilines (Table 2, entries 13 and
14) also led to the coupling products with similar efficiency
to those obtained with para- and meta-substituted anilines.
In general, anilines functionalized with electron-withdraw-
ing groups (e.g., CN, NO2, CF3) required slightly longer reac-
tion times compared to anilines functionalized with elec-
tron-donating groups. Further, tri-O-benzyl galactal (1c)
was subjected to the one-pot C-arylation with different ani-
lines under the optimized conditions to afford the desired
products 3ca–cc in 48–52% yields (Scheme 3).
R
O
t-BuONO, HBF4 (aq)
CH3CN/H2O, ~5 °C to RT, 30 min
R
O
O
BnO
BnO
OBn
Pd (OAc)2 (10 mol%)
dr: ≥ 19:1
(by NMR)
1e
OMe
NO2
O
O
O
O
O
BnO
BnO
BnO
3ec (6 h, 70%)
O
3ea (6 h, 72%)
3eb (6 h, 75%)
Scheme 6 Reaction of benzyl-protected D-rhamnal with different ani-
lines. See the general procedure for the reaction conditions
light, 2-deoxy C-arylated L-rhamnose derivatives 3da–dc
were obtained as single diastereomers (i.e.,  anomers) in
65–68% yields.
Among the different C-aryl glycosides, 2-deoxy C-aryl D-
rhamnose motifs are found in many natural products and
bioactive molecules.1,2 Hence, di-O-benzyl D-rhamnal (1e)
was synthesized from tri-O-acetyl glucal (Scheme 5) and
subjected to the C-arylation with different anilines under
Having studied the scope of different diazonium salts
with D-glucal and D-galactal, the developed one-pot meth-
odology was further evaluated with di-O-benzyl L-rhamnal
(1d) under the optimized conditions (Scheme 4). To our de-
O
O
1) PDC, Ac2O, CH2Cl2
83%
O
O
O
O
O
1) TFA, H2O
O
2) Ac2O, Py, DMAP
69% (over two steps)
2) NaBH4, EtOH
81%
O
HO
O
O
HO
4
OBn
O
OAc
OAc
OAc
OAc
O
1) 33% HBr/AcOH
1) NaOMe, MeOH
CH2Cl2, 5 h
BnO
AcO
AcO
2) Zn, NH4Cl, CH3CN
43% (over two steps)
2) NaH, BnBr, DMF
85%
OBn
1f
OAc
OAc
5
6
Scheme 7 Synthesis of tri-O-benzylD-altral from 1,2:5,6-di-O-isopropylidene--D-glucofuranose
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

E
A. K. Singh et al.
Paper
Synthesis
the optimized conditions (Scheme 6). The C-arylation reac-
tions proceeded smoothly and gave the desired products in
70–75% yields.
O
O
1) PhI(TFA)2, TEMPO
1 h, 49%
O
3) NaH, BnBr, DMF
BnO
BnO
BnO
2) LiAlH(O-t-Bu)3,
0 °C, overnight
75%
THF, 4 h, 40%
OH
OBn
OBn
To understand the stereospecificity of the reaction, we
have synthesized tri-O-benzyl D-altral (1f), (i.e., C-3 invert-
ed glucal) from 1,2:5,6-di-O-isopropylidene--D-glucofura-
nose (Scheme 7) and subjected it to the coupling reaction
with different anilines under the optimized conditions. To
our delight, the reactions proceeded smoothly and provided
-aryl glycosides 3fa–fg in good yields at room temperature
(Scheme 8). Likewise, di-O-benzyl 6-deoxy-L-allal (1g) (i.e.,
C-3 inverted L-rhamnal), prepared from di-O-benzyl L-
rhamnal, was subjected to the coupling reaction with 4-
methoxyaniline (2a) and 4-nitroaniline (2k) under the opti-
mized conditions (Scheme 9). As expected, the reactions
gave only the 2-deoxy -C-aryl glycosides 3ga and 3gb in
61% and 63% yields, respectively.
7
1g
1d
TBN, HBF4
AcCN/H2O
R
NH2
R = OMe (2a)
~5 °C to RT
Pd(OAc)2
R = NO2 (2k)
R
O
O
dr: ≥ 19:1
(by NMR)
BnO
R = OMe: 3ga (6 h, 61%)
R = NO2: 3gb (7 h, 63%)
Scheme 9 Synthesis and reactions of di-O-benzyl 6-deoxy-L-allal with
4-methoxyaniline and 4-nitroaniline
R1
NH2
R1
OBn
OBn
t-BuONO, HBF4 (aq)
CH3CN/H2O, ~5 °C to RT, 30 min
O
OBn
OBn
O
O
OH
Pd/C, H2
MeOH/EtOAc
AcOH
O
Ph
O
O
Ph
O
Ph
nBuLi, THF
–78 °C, 5 h
BnO
BnO
Pd (OAc)2 (10 mol%)
dr: ≥ 19:1
(by NMR)
OBn
BnO
BnO
HO
Ph3PCH3Br
78%
RT to 24 h
92%
1f
OBn
CH2
O
3ab
OMe
Cl
4b
4a
OBn
OBn
O
O
O
O
O
RMgBr
dry THF, –20 °C
BnO
BnO
BnO
O
OBn
3fa (8 h, 60%)
3fb (7 h, 63%)
3fc (7 h, 55%)
O
Ph
R = alkyl or aryl
Br
BnO
OBn
O
OBn
O
OH
4c–h
dr: ≥ 19:1 (by NMR)
R
BnO
O
BnO
O
OBn
OBn
OBn
3fd (6.5 h, 64%)
3fe (6.5 h, 68%)
O
Ph
O
Ph
O
Ph
Scheme 8 Reaction of tri-O-benzylD-altral with different anilines. See
the general procedure for the reaction conditions
BnO
BnO
BnO
OH
4c (2 h, 86%)
OH
4e (2.5 h, 70%)
OBn
OH
4d (2 h, 80%)
OBn
Having established a simple one-pot procedure, differ-
ent transformations of the synthesized 2,3-deoxy 3-keto
aryl C-glycoside 3ab were investigated (Scheme 10). The re-
duction of 3ab with Pd/C in the presence of H2 provided the
debenzylated product 4a in 92% yield. Wittig reaction of
3ab with methyltriphenylphosphonium bromide in the
presence of n-BuLi furnished the corresponding alkene 4b
in 80% yield. Treatment of 3ab with methylmagnesium bro-
mide gave 3-methyl-3-hydroxy C-glycoside 4c as a single
diastereomer in 86% yield. This reaction was extended to
other Grignard reagents to give the corresponding products
4d–h in yields ranging from 70–80% yield.
OBn
O
Ph
O
Ph
O
Ph
BnO
BnO
BnO
OH
OH
OH
4f (3 h, 75%)
4g (2 h, 70%)
4h (2 h, 76%)
Scheme 10 Different transformations of 2,3-deoxy 3-keto aryl C-gly-
coside 3ab
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

F
A. K. Singh et al.
Paper
Synthesis
Mechanism with glycal:
O
PdOAc
H
O
O
Bn
O
O
O
N2
BF4
O
O
O
O
syn-elimination
H2O
HBF4
I-1
Pd(OAc)2
– HPdOAc
– BnOH
(or)
OBn
syn-addition
– N2, – BF4
Bn
OH
BF4
Bn
H
I-3
O
X (α-isomer)
dr: ≥ 19:1
I-5
I-4
PdOAc
H
O
Bn
I-2
Mechanism with anti-glycal:
O
O
PdOAc
H
O
O
O
O
N2
HBF4
H2O
BF4
Bn
syn-elimination
– HPdOAc
I-6
or
Pd(OAc)2
OBn
O
Bn
syn-addition
– N2, – BF4
Y (β-isomer)
dr: ≥ 19:1
O
I-8
PdOAc
H
O
Bn
I-7
Scheme 11 Plausible mechanisms for the palladium-catalyzed C-arylation of glycals and anti-glycals
A plausible mechanism for the palladium-catalyzed ste-
reospecific C-arylation of glycals is shown in Scheme 11.
Mechanism with glycals: The oxidative syn-addition of pal-
ladium to the aryldiazonium salt in the presence of the gly-
cal would provide intermediates I-1 or I-2. In the next step,
intermediate I-1 or I-2 undergoes syn--elimination to
form enol ether I-3. However, in the case of intermediate I-
2, there is no possibility for the syn--elimination due to
the lack of a syn--hydrogen. Therefore, we believe that
only intermediate I-1 is formed during the reaction. In the
presence of HBF4/water, enol ether I-3 undergoes hydrolysis
via intermediate I-4 to give enol I-5, which leads to the de-
sired product X [i.e., -C-aryl glycosides, (dr ≥ 19:1)]. Mech-
anism with anti-glycals: the reaction of C-3 inverted glycals
(i.e., anti-glycals) with the aryldiazonium salt and palladi-
um acetate would similarly provide intermediates I-6 or I-7.
Due to the lack of a syn--hydrogen in I-7, only intermedi-
ate I-6 is formed. This intermediate undergoes syn--elimi-
nation to provide the -C-aryl glycosides (dr ≥ 19:1) ste-
reospecifically as shown in the mechanism.
tions proceeded at room temperature and provided the de-
sired aryl C-glycosides in good yields. The configuration at
the C-3 position in the glycals dictates the anomeric selec-
tivity (i.e., either  or ).
All reactions were carried out in oven-dried glassware. Starting mate-
rials 1a–d were prepared using literature procedures.7 Starting mate-
rials 1e–g have been prepared using modified procedures as de-
scribed in the experimental section. Anilines were purchased from
Aldrich and Alfa Aesar chemicals. Thin-layer chromatography was
performed using pre-coated plates obtained from E. Merck (TLC silica
gel 60 F254). TLC plates were visualized by exposure to ultraviolet
light (UV), then further analyzed by staining (5% H2SO4 in MeOH) and
charring. Column chromatography was performed on Sigma-Aldrich
silica gel (100–200 mesh) using mixtures of ethyl acetate and hexane
as eluents. Melting points were obtained using a Kruss Optronic
KSP1D Automatic melting point apparatus. Optical rotations were re-
corded using a Jasco P-2000 polarimeter. IR spectra for new com-
pounds were recorded using a PerkinElmer spectrometer. NMR spec-
tra were recorded on a Bruker Avance 500 MHz NMR spectrometer.
The 1H and 13C NMR spectra are reported as chemical shifts () in
parts per million (ppm), with TMS (0.00 ppm) or residual undeuterat-
ed CDCl3 (7.26 ppm) (for 1H NMR spectra) and the CDCl3 signal at 77.0
ppm (for 13C NMR spectra) used as references. High-resolution mass
spectrometry (HRMS) was performed using a Waters Quattro Micro V
In summary, an efficient one-pot procedure for the ste-
reospecific synthesis of - and -aryl C-glycosides using
glycals and anilines in the presence of palladium acetate
and tert-butyl nitrite has been demonstrated. All the reac-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

G
A. K. Singh et al.
Paper
Synthesis
4.1 spectrometer. HPLC analysis was performed on an Agilent
LC/192168254.11 instrument. A C-8 reverse-phase column was used
for the analysis with acetonitrile/water (70:30) as the solvent. The
flow rate was maintained at 1 mL/min. A 10 L sample was injected
for each analysis.
(AIBN) (117 mg, 712 mol, 0.1 equiv). The resulting mixture was re-
fluxed at 100 °C for 3 h and then cooled to room temperature. The sol-
vent was removed under reduced pressure and the residue dissolved
in ethyl acetate and washed with water. The organic layer was evapo-
rated and the residue was purified by silica gel chromatography (pe-
troleum ether/EtOAc, 80:20) to afford 6-deoxy glucal 3.
3,4-Di-O-acetyl-6-O-tosyl-D-glucal (1)16
27
Yield: 1.49 g (98%); colorless liquid; []D –56.1 (c 1.0, CHCl3) {Lit.18
[]D25 –54.5 (c 0.98, CHCl3)}.
Potassium carbonate (0.5 g, 3.6 mmol, 0.1 equiv) was added to a solu-
tion of tri-O-acetyl-D-glucal (10.0 g, 36.7 mmol, 1.0 equiv) in MeOH
(70 mL) and the mixture was stirred at room temperature for 4 h. Af-
ter completion, the mixture was filtered through Celite and concen-
trated on a rotary evaporator to give D-glucal as a viscous oil in quan-
titative yield (~5.3 g). The obtained crude product (5.3 g, 36.4 mmol)
was dissolved in a mixture of dry CH2Cl2 (73 mL) and dry pyridine (73
mL), cooled to 0 °C, and treated with p-toluenesulfonyl chloride (10.4
g, 54.6 mmol, 1.5 equiv). The resulting mixture was stirred for 8 h at
room temperature and then cooled to 0 °C. Water (30 mL) was added
and the mixture stirred for 30 min at 0 °C. The reaction mixture was
diluted with CH2Cl2 and the organic layer was separated, washed with
water and brine, and then dried over Na2SO4 and concentrated to af-
ford the desired 6-O-tosylate which was directly used in the next step
without further purification. The crude tosylate was stirred in pyri-
dine (50 mL) and then Ac2O (50 mL, 439 mmol) was added slowly at
room temperature followed by DMAP (0.44 g, 3.6 mmol). The mixture
was allowed to stir for 24 h at room temperature and then diluted
with ethyl acetate, washed with water and brine, and dried over an-
hydrous Na2SO4. The organic layer was evaporated and the residue
purified by silica gel chromatography (petroleum ether/EtOAc, 80:20)
to give compound 1.
1H NMR (500 MHz, CDCl3):  = 6.42 (dd, J = 6.0, 1.5 Hz, 1 H), 5.34–5.32
(m, 1 H), 5.01 (dd, J = 8.5, 6.5 Hz, 1 H), 4.76 (dd, J = 6.5, 3.0 Hz, 1 H),
4.12–4.07 (m, 1 H), 2.07 (s, 3 H), 2.03 (s, 3 H), 1.30 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 170.6, 169.8, 145.9, 98.7, 72.4, 71.8,
68.2, 21.0, 20.8, 16.5.
3,4-Di-O-benzyl-D-rhamnal (1e)7
Compound 3 (1 g, 4.67 mmol) was stirred in MeOH (30 mL) at 0 °C
and then NaOMe (22 mg, 0.46 mmol) was added. The resulting mix-
ture was stirred for 3 h and the solvent was evaporated to dryness.
Dry DMF (15 mL) was added to the residue and the mixture was
cooled to 0 °C. Subsequently, NaH (447 mg, 60% in mineral oil, 18
mmol) was added portionwise followed by stirring of the mixture for
20 min at the same temperature. Benzyl bromide (1.66 mL, 14 mmol)
was then slowly added dropwise and the resulting mixture stirred
overnight. The reaction mixture was quenched with saturated aque-
ous NH4Cl (6 mL) and diluted with ethyl acetate (25 mL). The organic
phase was washed with water and brine, and then dried over anhy-
drous Na2SO4. The organic layer was evaporated under reduced pres-
sure and the residue was purified by silica gel column chromatogra-
phy (hexane/ethyl acetate, 90:10) to afford 1e.
Yield: 9.1 g (65%); white solid; mp 104 °C (Lit.17 106–107 °C); []D
27
20
Yield: 1.2 g (83%); colorless oil; []D27 –30.1 (c 1.0, CHCl3) {Lit.19 []D
+28.9 (c 1.0, CHCl3) {Lit.18 []D25 +7.1 (c 0.51, CHCl3)}.
–33 (c 1.0, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 7.73 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 8.0
Hz, 2 H), 6.28 (dd, J = 6.0, 1.0 Hz, 1 H), 5.20 (t, J = 4.0 Hz, 1 H), 5.07–
5.05 (m, 1 H), 4.75 (dd, J = 6.5, 3.5 Hz, 1 H), 4.21–4.16 (m, 2 H), 4.16–
4.11 (m, 1 H), 2.38 (s, 3 H), 1.97 (s, 3 H), 1.96 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 170.2, 169.4, 145.2, 145.1, 132.5,
129.8, 128.0, 98.9, 73.1, 66.9, 66.5, 66.3, 21.6, 20.9, 20.7.
1H NMR (500 MHz, CDCl3):  = 7.36–7.27 (m, 10 H), 6.35 (d, J = 6.0 Hz,
1 H), 4.89–4.84 (m, 2 H), 4.70 (d, J = 11.5 Hz, 1 H), 4.65 (d, J = 12.0 Hz,
1 H), 4.57 (d, J = 11.0 Hz, 1 H), 4.20 (d, J = 6.5 Hz, 1 H), 3.97–3.92 (m, 1
H), 3.48 (dd, J = 8.5, 6.5 Hz, 1 H), 1.37 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 144.7, 138.4, 138.2, 128.38, 128.37,
127.93, 127.75, 127.72, 127.60, 100.1, 79.5, 76.4, 74.0, 73.9, 72.0, 70.5,
17.4.
6-Iodo-3,4-di-O-acetyl-D-glucal (2)16
To a solution of 1 (9.1 g, 23.6 mmol, 1.0 equiv) in DMF (118 mL) was
added tetrabutylammonium iodide (TBAI) (8.72 g, 23.6 mmol, 1.0
equiv) and KI (11.7 g, 71 mmol, 3.0 equiv). The solution was stirred at
60 °C for 12 h and then cooled to room temperature, diluted with wa-
ter and extracted using EtOAc. The combined organic layer was
washed with saturated aqueous Na2S2O3 and brine, and then dried
over anhydrous Na2SO4. The organic layer was evaporated and the res-
idue was purified by silica gel chromatography (petroleum ether/EtOAc,
90:10) to give 2.
1,2:5,6-Di-O-isopropylidene--D-allofuranose (4)20,21
A mixture of pyridinium dichromate (10.8 g, 28.7 mmol) and acetic
anhydride (11 mL, 116 mmol) was stirred in dichloromethane (100
mL) and then a solution of 1,2:5,6-di-O-isopropylidene--D-glucofu-
ranose (10.0 g, 3.84 mmol) in dichloromethane (30 mL) was added.
The resulting mixture was refluxed for 2 h at 40 °C and cooled to
room temperature. The solvent was evaporated, diluted with ethyl ac-
etate (100 mL) and filtered through Celite. The filtrate was concen-
trated under reduced pressure to give the corresponding ketone as a
viscous oil (8.20 g, 83%) which was used in the next step without fur-
ther purification.
25
Yield: 7.7 g (96%); viscous oil; []D27 –33.7 (c 1.0, CHCl3) {Lit.18 []D
–35.2 (c 1.02, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 6.46–6.42 (m, 1 H), 5.27–5.18 (m, 2 H),
4.84–4.79 (m, 1 H), 4.08–4.02 (m, 1 H), 3.41–3.27 (m, 2 H), 2.07–1.99
(m, 6 H).
13C NMR (125 MHz, CDCl3):  = 170.2, 169.4, 145.3, 98.8, 74.7, 69.7,
66.5, 20.9, 20.8, 1.9.
To a solution of the ketone (8.0 g, 31.0 mmol) dissolved in 56% aq
EtOH (43 mL) and cooled to 0 °C was added sodium borohydride (1.29
g, 34.0 mmol) portionwise. The reaction mixture was brought to
room temperature and stirred for 3 h. After completion, the reaction
mixture was diluted with dichloromethane (50 mL) and washed with
water. The combined organic layers were dried over anhydrous
Na2SO4 and evaporated to dryness. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate, 75:25) to provide
1,2:5,6-di-O-isopropylidene--D-allofuranose (4).
3,4-Di-O-acetyl-D-rhamnal (3)18
To a solution of 6-iodo-3,4-di-O-acetyl-D-glucal (2) (2.42 g, 7.12
mmol, 1.0 equiv) in dry toluene (50 mL) was added Bu3SnH (3.12 g,
2.88 mL, 10.7 mmol, 1.5 equiv) and 2,2′-azobis(isobutyronitrile)
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

H
A. K. Singh et al.
Paper
Synthesis
27
Yield: 6.5 g (81%); white solid; mp 74 °C (Lit.22 73 °C); []D +54 (c
cooled to 0 °C and NaH (528 mg, 60% in mineral oil, 22.0 mmol) was
added portionwise. The resulting mixture was stirred for 20 min at
the same temperature and then benzyl bromide (1.74 mL, 15 mmol)
was slowly added dropwise. The mixture was stirred overnight and
then quenched with saturated aqueous NH4Cl (8 mL) and diluted with
ethyl acetate (50 mL). The organic phase was washed with H2O and
brine and then dried over anhydrous Na2SO4. The organic layer was
evaporated under reduced pressure and the crude product was puri-
fied by silica gel column chromatography (hexane/ethyl acetate,
90:10) to afford 3,4,6-tri-O-benzyl-D-altral (1f).
0.1, CHCl3) {Lit.22 []D25 +39.8 (c 0.42, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 5.81 (d, J = 3.5 Hz, 1 H), 4.63–4.61 (m, 1
H), 4.33–4.29 (m, 1 H), 4.10–4.00 (m, 3 H), 3.84–3.81 (m, 1 H), 1.58 (s,
3 H), 1.47 (s, 3 H), 1.38 (d, J = 6.5 Hz, 6 H).
13C NMR (125 MHz, CDCl3):  = 112.8, 109.8, 103.8, 79.6, 78.9, 75.5,
72.4, 65.8, 26.5, 26.4, 26.2, 25.2.
D-Allopyranose Pentaacetate (5)21
1,2:5,6-Di-O-isopropylidene--D-allofuranose (4) (6.00 g, 23.05
mmol) was dissolved in a mixture of trifluoroacetic acid/water (1:1,
24 mL) and stirred at room temperature for 24 h. After completion,
the solvent was removed on a rotary evaporator and co-evaporated
with toluene. The resulting yellow syrup was dissolved in acetic anhy-
dride/pyridine mixture (1:1, 80 mL) and stirred at room temperature
overnight. The mixture was concentrated in vacuo and co-evaporated
with toluene. The resulting white solid was dissolved in ethyl acetate
and washed with 1 M hydrochloric acid, saturated aqueous sodium
bicarbonate solution and brine. The organic layer was dried over an-
hydrous Na2SO4, concentrated and purified by silica gel column chro-
matography (hexane/ethyl acetate, 80:20) to afford D-allopyranose
pentaacetate as a mixture of / anomers 5.
Yield: 1.3 g (85%); colorless oil; []D27 +71.1 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3):  = 7.29–7.15 (m, 15 H), 6.38 (dd, J = 6.0,
2.5 Hz, 1 H), 4.82–4.79 (m, 1 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.57–4.53
(m, 3 H), 4.49 (d, J = 12.0 Hz, 1 H), 4.39 (d, J = 11.5 Hz, 1 H), 4.23–4.21
(m, 1 H), 3.89–3.86 (m, 1 H), 3.768–3.763 (m, 2 H), 3.72–3.69 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 146.6, 138.6, 138.0, 137.8, 128.3,
127.9, 127.8, 127.7, 127.67, 127.56, 127.53, 98.0, 73.8, 73.5, 73.0, 71.2,
70.3, 68.8, 65.4.
Di-O-Benzyl-6-deoxy-L-allal (1g)24
3,4-Di-O-benzyl-L-rhamnal (1d) (1.50 g, 4.83 mmol) was stirred in
CH2Cl2 (35 mL) then PhI(TFA)2 (4.16 g, 9.67 mmol), 2,2,6,6-tetrameth-
ylpiperidine 1-oxyl (TEMPO) (151 mg, 0.96 mmol) and water (87 L,
4.83 mmol) were added at 0 °C under an argon atmosphere. The re-
sulting mixture was stirred for 30 min at the same temperature. After
completion (monitored by TLC), the reaction mixture was quenched
with a saturated solution of NaHCO3 and extracted with CH2Cl2
(twice). The combined organic layers were washed with brine and
dried over anhydrous Na2SO4. The organic layer was evaporated and
the residue was purified by silica gel column chromatography (hex-
ane/ethyl acetate, 85:15) to give 3-keto L-rhamnal (0.52 g, 49%). To a
solution of 3-keto L-rhamnal (0.50 g, 2.29 mmol) in dry THF (10 mL)
at 0 °C under an argon atmosphere was added a solution of lithium
tri(tert-butoxy)aluminum hydride (0.73 g, 2.98 mmol) in THF. The re-
sulting mixture was brought to room temperature and stirred for 4 h.
After completion, the reaction mixture was quenched with saturated
NH4Cl solution and extracted with ethyl acetate (twice). The com-
bined organic layers were washed with brine and dried over anhy-
drous Na2SO4. The organic layer was evaporated and the residue puri-
fied by silica gel column chromatography (hexane/ethyl acetate,
85:15) to afford 4-O-benzyl 6-deoxy-L-allal (7) (0.204 g, 40%). Com-
pound 7 (200 mg, 0.908 mmol) was stirred in dry DMF (8 mL) at 0 °C
and NaH (60% suspension in paraffin oil, 43.00 mg, 1.82 mmol) was
added followed by benzyl bromide (161.0 L, 1.36 mmol). The reac-
tion mixture was then stirred at room temperature for 10 h. After
completion, the reaction mixture was quenched with ice water and
extracted with ethyl acetate. The combined organic layers were
washed with brine and then dried over anhydrous Na2SO4. The sol-
vent was evaporated and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 90:10) to provide 1g.
Yield: 6.2 g (69%); colorless syrup.
1H NMR (500 MHz, CDCl3):  = 6.11–5.94 (m, 1 H), 5.65–5.44 (m, 1 H),
5.27–4.92 (m, 2 H), 4.36–4.00 (m, 3 H), 2.11 (s, 3 H), 2.07 (s, 3 H), 2.03
(s, 3 H), 1.96–1.95 (m, 6 H).
13C NMR (125 MHz, CDCl3):  (/ anomers) = 170.4, 170.2, 169.6,
169.5, 169.1, 169.0, 168.9, 168.8, 168.7, 98.1, 89.8, 79.8, 77.2, 74.1,
70.85, 70.81, 67.99, 67.90, 65.4, 61.9, 61.6, 20.75, 20.70, 20.58, 20.52,
20.4, 20.3, 20.25, 20.25.
3,4,6-Tri-O-acetyl-D-altral (6)23
D-Allopyranose pentaacetate (5) (4.00 g, 10.25 mmol) was dissolved
in CH2Cl2 (20 mL) and HBr solution (33 wt% in acetic acid, 22.60 mL,
92.00 mmol) was added at 0 °C. The resulting solution was stirred for
5 h at room temperature. After completion, the reaction mixture was
diluted with CH2Cl2 (25 mL) and washed successively with a saturated
solution of sodium bicarbonate and brine. The organic layer was dried
over anhydrous Na2SO4 and concentrated. The crude allopyranosyl
bromide was dissolved in CH3CN (25 mL) and zinc dust (5.0 g, 76.80
mmol) and ammonium chloride (4.10 g, 76.80 mmol) were added.
The resulting mixture was stirred at 50 °C for 2.5 h. After completion,
the reaction mixture was filtered and the filtrate was concentrated
and purified by silica gel column chromatography (hexane/ethyl ace-
tate, 85:15) to afford 3,4,6-tri-O-acetyl-D-altral (6).
Yield: 1.2 g (43%); colorless oil; []D27 = +58.1 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3):  = 6.47 (d, J = 6.0 Hz, 1 H), 5.38 (dd, J = 6.0,
4.0 Hz, 1 H), 5.07 (dd, J = 11.0, 4.0 Hz, 1 H), 4.86 (t, J = 6.0 Hz, 1 H),
4.31–4.19 (m, 3 H), 2.02 (s, 6 H), 1.97 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 170.5, 170.2, 169.3, 147.7, 97.4, 70.4,
66.3, 62.5, 61.8, 20.9, 20.6, 20.5.
Yield: 210 mg (75%); colorless syrup; []D27 –250 (c 1.0, CHCl3) {Lit.25
[]D20 –259.4 (c 1.1, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 7.35–7.26 (m, 10 H), 6.35 (dd, J = 6.0,
1.5 Hz, 1 H), 4.88–4.84 (m, 2 H), 4.69 (d, J = 11.0 Hz, 1 H), 4.65 (d, J =
11.5 Hz, 1 H), 4.56 (d, J = 11.5 Hz, 1 H), 4.21–4.19 (m, 1 H), 3.97–3.91
(m, 1 H), 3.48 (dd, J = 9.0, 6.5 Hz, 1 H), 1.38 (d, J = 6.5 Hz, 3 H).
3,4,6-Tri-O-benzyl-D-altral (1f)23
3,4,6-Tri-O-acetyl-D-altral (6) (1.0 g, 3.6 mmol) was stirred in MeOH
(20 mL) at 0 °C and NaOMe (19.0 mg, 0.37 mmol) was added. The re-
sulting mixture was stirred for 3 h and then the solvent was evaporat-
ed to dryness. Dry DMF (15 mL) was added and the solution was
13C NMR (125 MHz, CDCl3):  = 144.7, 138.3, 138.2, 128.36, 128.35,
127.9, 127.7, 127.5, 100.0, 79.4, 76.4, 74.0, 73.9, 70.4, 17.4.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

I
A. K. Singh et al.
Paper
Synthesis
C-Glycosides 3; General Procedure
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-bromophe-
nyl)dihydro-2H-pyran-4(3H)-one (3ad)7
Aniline 2a–k (0.25 mmol, 2.0 equiv) was dissolved in a mixture of
acetonitrile/water (3:1, 4 mL) and stirred at ~5 °C (ice bath). Next, 48%
aq HBF4 (2.0 equiv) was added. After 5 min, t-BuONO (0.25 mmol, 2.0
equiv) was added and the resulting mixture was allowed to attain
room temperature. After 30 min, glycal 1a–g (0.125 mmol) and palla-
dium acetate (2.80 mg, 10 mol%) were added at room temperature
and the mixture was stirred for the appropriate amount of time. After
completion, the reaction mixture was diluted with ethyl acetate and
washed with water. The organic layer was dried over Na2SO4, concen-
trated and purified by column chromatography on silica gel.
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
27
Yield: 45 mg (75%); white foam; Rf = 0.56 (20% EtOAc/hexane); []D
+57 (c 0.1, CHCl3) {Lit.12 []D19 +104.5 (c 0.2, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 7.39–7.36 (m, 2 H), 7.26–7.16 (m, 12
H), 5.33 (dd, J = 6.0, 3.5 Hz, 1 H), 4.75 (d, J = 11.0 Hz, 1 H), 4.49 (d, J =
12.0 Hz, 1 H), 4.40 (d, J = 12.5 Hz, 1 H), 4.34 (d, J = 11.0 Hz, 1 H), 4.14
(d, J = 8.5 Hz, 1 H), 3.65–3.56 (m, 3 H), 2.99–2.91 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 205.9, 137.74, 137.71, 137.2, 131.8,
129.0, 128.39, 128.36, 128.1, 127.9, 127.8, 127.7, 122.3, 79.4, 75.0,
74.6, 73.5, 73.3, 69.1, 43.9.
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-methoxy-
phenyl)dihydro-2H-pyran-4(3H)-one (3aa)7
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-chlorophe-
nyl)dihydro-2H-pyran-4(3H)-one (3ae)7
26
Yield: 41 mg (76%); white foam; Rf = 0.40 (20% EtOAc/hexane); []D
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
+126 (c 0.1, CHCl3) {Lit.12 []D21 +120.8 (c 1.4, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 7.26–7.18 (m, 12 H), 6.79–6.76 (m, 2
H), 5.36 (dd, J = 6.5, 2.5 Hz, 1 H), 4.77 (d, J = 11.0 Hz, 1 H), 4.51 (d, J =
12.5 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.35 (d, J = 11.0 Hz, 1 H), 4.16
(d, J = 8.5 Hz, 1 H), 3.70 (s, 3 H), 3.63–3.54 (m, 3 H), 3.01 (dd, J = 14.5,
3.5 Hz, 1 H), 2.97–2.93 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 206.7, 159.4, 137.9, 137.4, 130.6,
128.8, 128.37, 128.35, 128.1, 127.89, 127.83, 127.71, 114.0, 79.7, 74.8,
74.2, 73.5, 73.4, 69.1, 55.2, 44.0.
26
Yield: 35 mg (65%); white foam; Rf = 0.56 (20% EtOAc/hexane); []D
+112 (c 0.1, CHCl3).
1H NMR (500 MHz, CDCl3):  = 7.34–7.24 (m, 14 H), 5.43 (dd, J = 6.5,
3.5 Hz, 1 H), 4.82 (d, J = 11.5 Hz, 1 H), 4.57 (d, J = 12.0 Hz, 1 H), 4.47 (d,
J = 12.0 Hz, 1 H), 4.41 (d, J = 11.0 Hz, 1 H), 4.22 (d, J = 9.0 Hz, 1 H),
3.71–3.63 (m, 3 H), 3.08–2.99 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 206.0, 137.7, 137.2, 137.1, 134.1,
128.8, 128.7, 128.38, 128.35, 128.1, 127.9, 127.79, 127.75, 79.4, 77.2,
74.8, 74.5, 73.5, 73.3, 69.0, 43.9.
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-phenyldihy-
dro-2H-pyran-4(3H)-one (3ab)7
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-fluorophe-
nyl)dihydro-2H-pyran-4(3H)-one (3af)7
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
27
Yield: 30 mg (60%); white foam; Rf = 0.62 (20% EtOAc/hexane); []D
+140 (c 0.1, CHCl3) {Lit.12 []D19 = +85.3 (c 0.2, CHCl3)}.
26
Yield: 38 mg (72%); white foam; Rf = 0.56 (20% EtOAc/hexane); []D
1H NMR (500 MHz, CDCl3):  = 7.31–7.30 (m, 2 H), 7.27–7.19 (m, 13
H), 5.41 (dd, J = 6.5, 2.5 Hz, 1 H), 4.76 (d, J = 11.0 Hz, 1 H), 4.52 (d, J =
12.2 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.34 (d, J = 11.0 Hz, 1 H), 4.17
(d, J = 8.5 Hz, 1 H), 3.66–3.56 (m, 3 H), 3.05 (dd, J = 14.5, 3.0 Hz, 1 H),
2.99–2.95 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 206.4, 138.5, 137.8, 137.3, 128.7,
128.37, 128.35, 128.2, 128.1, 127.9, 127.8, 127.7, 127.3, 79.5, 75.1,
74.5, 73.5, 73.4, 69.0, 43.8.
+144 (c 0.1, CHCl3).
1H NMR (500 MHz, CDCl3):  = 7.29–7.17 (m, 12 H), 6.95–6.92 (m, 2
H), 5.36 (dd, J = 6.0, 3.0 Hz, 1 H), 4.75 (d, J = 11.0 Hz, 1 H), 4.50 (d, J =
12.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.35 (d, J = 11.5 Hz, 1 H), 4.15
(d, J = 9.0 Hz, 1 H), 3.64–3.56 (m, 3 H), 3.01–2.92 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 206.1, 162.4 (d, J = 245 Hz), 137.7,
137.2, 134.4, 129.25 (d, J = 8 Hz), 128.38, 128.36, 128.1, 127.88 (d, J =
24 Hz), 127.8, 115.6, 115.4, 79.5, 74.7, 74.6, 73.5, 73.3, 69.1, 44.0.
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(p-tolyl)dihy-
dro-2H-pyran-4(3H)-one (3ac)7
(2R,3R,6S)-6-(4-Acetylphenyl)-3-(benzyloxy)-2-[(benzyloxy)meth-
yl]dihydro-2H-pyran-4(3H)-one (3ag)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
The product was purified by column chromatography on silica gel
(20% EtOAc/hexane).
26
Yield: 41 mg (79%); white foam; Rf = 0.60 (20% EtOAc/hexane); []D
26
Yield: 35 mg (63%); white foam; Rf = 0.50 (20% EtOAc/hexane); []D
+60.0 (c 0.05, CHCl3).
+89 (c 0.1, CHCl3).
IR (neat): 2811–2971, 1721, 1680, 1130, 881 cm–1
1H NMR (500 MHz, CDCl3):  = 7.26–7.18 (m, 12 H), 7.06–7.05 (m, 2
H), 5.37 (dd, J = 6.5, 2.5 Hz, 1 H), 4.77 (d, J = 11.5 Hz, 1 H), 4.51 (d, J =
12.5 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.35 (d, J = 11.0 Hz, 1 H), 4.15
(d, J = 9.0 Hz, 1 H), 3.65–3.55 (m, 3 H), 3.02 (dd, J = 14.5, 3.0 Hz, 1 H),
2.97–2.92 (m, 1 H), 2.23 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 206.5, 137.9, 137.9, 137.4, 135.5,
129.3, 128.37, 128.34, 128.1, 127.88, 127.83, 127.7, 127.4, 79.6, 75.0,
74.4, 73.5, 73.4, 69.1, 44.0, 21.0.
.
1H NMR (500 MHz, CDCl3):  = 7.85 (d, J = 8.5 Hz, 2 H), 7.41 (d, J = 8.5
Hz, 2 H), 7.27–7.18 (m, 10 H), 5.43 (dd, J = 6.5, 4.0 Hz, 1 H), 4.75 (d, J =
11.0 Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.41 (d, J = 12.0 Hz, 1 H), 4.34
(d, J = 11.5 Hz, 1 H), 4.16 (d, J = 8.0 Hz, 1 H), 3.66–3.63 (m, 1 H), 3.614–
3.611 (m, 2 H), 3.04 (dd, J = 14.5, 3.5 Hz, 1 H), 2.98 (dd, J = 14.5, 6.5 Hz,
1 H), 2.50 (s, 3 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

J
A. K. Singh et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3):  = 205.7, 197.5, 143.8, 137.6, 137.1,
136.7, 128.7, 128.4, 128.3, 128.1, 127.9, 127.8, 127.4, 79.3, 75.3, 74.8,
73.5, 73.3, 69.1, 43.9, 26.6.
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-nitrophe-
nyl)dihydro-2H-pyran-4(3H)-one (3ak)8
The product was purified by column chromatography on silica gel
(20% EtOAc/hexane).
HRMS (ESI): m/z [M + H]+ calcd for C28H29O5: 445.2015; found:
445.2021.
Yield: 34 mg (61%); white foam; cc: 20% EtOAc/hexane; Rf = 0.45 (20%
EtOAc/hexane); []D27 +39 (c 0.1, CHCl3) {Lit.12 []D23 +74.1 (c 2.3, CH-
Cl3)}.
1H NMR (500 MHz, CDCl3):  = 8.12–8.10 (m, 2 H), 7.49–7.48 (m, 2 H),
7.27–7.17 (m, 10 H), 5.44 (t, J = 5.5 Hz, 1 H), 4.72 (d, J = 11.5 Hz, 1 H),
4.49 (d, J = 12.5 Hz, 1 H), 4.41 (d, J = 12.0 Hz, 1 H), 4.34 (d, J = 11.5 Hz,
1 H), 4.13 (d, J = 8.0 Hz, 1 H), 3.72–3.69 (m, 1 H), 3.62–3.61 (m, 2 H),
3.02–2.93 (m, 2 H).
4-{(2S,5R,6R)-5-(Benzyloxy)-6-[(benzyloxy)methyl]-4-oxotetrahy-
dro-2H-pyran-2-yl}benzonitrile (3ah)7
The product was purified by column chromatography on silica gel
(20% EtOAc/hexane).
27
Yield: 32 mg (60%); white foam; Rf = 0.25 (20% EtOAc/hexane); []D
+97 (c 0.1, CHCl3).
13C NMR (125 MHz, CDCl3):  = 205.0, 147.5, 146.1, 137.5, 136.9,
128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 123.8, 79.0, 75.9, 74.3,
73.5, 73.1, 69.2, 44.0.
1H NMR (500 MHz, CDCl3):  = 7.56–7.54 (m, 2 H), 7.42 (d, J = 8.5 Hz, 2
H), 7.27–7.19 (m, 10 H), 5.39 (t, J = 5.5 Hz, 1 H), 4.72 (d, J = 11.5 Hz, 1
H), 4.49 (d, J = 12.5 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.34 (d, J = 11.0
Hz, 1 H), 4.12 (d, J = 8.5 Hz, 1 H), 3.69–3.67 (m, 1 H), 3.61–3.60 (m, 2
H), 3.00–2.91 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 205.1, 144.1, 137.5, 137.0, 132.4,
128.42, 128.39, 128.1, 128.0, 127.8, 127.7, 118.3, 112.0, 79.1, 75.8,
74.5, 73.5, 73.2, 69.2, 43.9.
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(3-chlorophe-
nyl)dihydro-2H-pyran-4(3H)-one (3al)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
27
Yield: 37 mg (70%); colorless oil; Rf = 0.64 (20% EtOAc/hexane); []D
Methyl 4-{(2S,5R,6R)-5-(Benzyloxy)-6-[(benzyloxy)methyl]-4-oxo-
tetrahydro-2H-pyran-2-yl}benzoate (3ai)7
+67 (c 0.1, CHCl3).
IR (neat): 2931, 2797, 1724, 1488, 1120, 754 cm–1
.
The product was purified by column chromatography on silica gel
(20% EtOAc/hexane).
1H NMR (500 MHz, CDCl3):  = 7.32 (s, 1 H), 7.29–7.17 (m, 13 H), 5.35
(dd, J = 6.0, 3.5 Hz, 1 H), 4.75 (d, J = 11.0 Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1
H), 4.40 (d, J = 12.0 Hz, 1 H), 4.34 (d, J = 11.0 Hz, 1 H), 4.15 (d, J = 8.5
Hz, 1 H), 3.69–3.66 (m, 1 H), 3.64–3.58 (m, 2 H), 3.00 (dd, J = 14.5, 3.5
Hz, 1 H), 2.95–2.91 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 205.7, 140.7, 137.6, 137.1, 134.8,
129.9, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.4, 125.2, 79.3, 75.1,
74.5, 73.5, 73.3, 69.1, 43.8.
27
Yield: 37 mg (64%); white foam; Rf = 0.40 (20% EtOAc/hexane); []D
+62 (c 0.1, CHCl3).
1H NMR (500 MHz, CDCl3):  = 7.94–7.91 (m, 2 H), 7.39 (d, J = 8.5 Hz, 2
H), 7.27–7.17 (m, 10 H), 5.42 (dd, J = 6.5, 4.0 Hz, 1 H), 4.74 (d, J = 11.5
Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.34 (d, J =
11.5 Hz, 1 H), 4.15 (d, J = 8.5 Hz, 1 H), 3.83 (s, 3 H), 3.68–3.65 (m, 1 H),
3.63–3.58 (m, 2 H), 3.04 (dd, J = 14.5, 3.5 Hz, 1 H), 2.98–2.94 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 205.7, 166.5, 143.7, 137.6, 137.1,
129.96, 129.90, 128.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.1, 79.3,
75.2, 74.8, 73.5, 73.2, 69.1, 52.1, 43.9.
HRMS (ESI): m/z [M + H]+ calcd for C26H26ClO4: 437.1520; found:
437.1511.
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(3-nitrophe-
nyl)dihydro-2H-pyran-4(3H)-one (3am)
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-[4-(trifluoro-
methyl)phenyl]dihydro-2H-pyran-4(3H)-one (3aj)
The product was purified by column chromatography on silica gel
(20% EtOAc/hexane).
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
27
Yield: 33 mg (59%); yellow oil; Rf = 0.42 (20% EtOAc/hexane); []D
+89 (c 0.1, CHCl3).
27
Yield: 36 mg (61%); white foam; Rf = 0.52 (20% EtOAc/hexane); []D
IR (neat): 2911, 2747, 1724, 1537, 1358, 1120 cm–1
.
+87.0 (c 0.1, CHCl3).
1H NMR (500 MHz, CDCl3):  = 8.214–8.211 (m, 1 H), 8.08–8.06 (m, 1
H), 7.64–7.62 (m, 1 H), 7.45 (t, J = 7.5 Hz, 1 H), 7.27–7.19 (m, 10 H),
5.45 (t, J = 5.5 Hz, 1 H), 4.73 (d, J = 11.5 Hz, 1 H), 4.51 (d, J = 12.5 Hz, 1
H), 4.41 (d, J = 12.0 Hz, 1 H), 4.35 (d, J = 11.5 Hz, 1 H), 4.15 (dd, J = 8.0,
0.5 Hz, 1 H), 3.75–3.72 (m, 1 H), 3.64–3.63 (m, 2 H), 3.03 (dd, J = 15.0,
5.0 Hz, 1 H), 2.98–2.94 (m, 1 H).
IR (neat): 2911, 2791, 1718, 1130, 881 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.52–7.51 (m, 2 H), 7.44–7.42 (m, 2 H),
7.27–7.17 (m, 10 H), 5.43–5.41 (m, 1 H), 4.74 (d, J = 11.0 Hz, 1 H), 4.50
(d, J = 12.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.34 (d, J = 11.0 Hz, 1 H),
4.15 (d, J = 8.5 Hz, 1 H), 3.66–3.58 (m, 3 H), 3.04–2.94 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 205.6, 142.6, 137.6, 137.1, 130.33 (q,
J = 32.5 Hz), 128.4, 128.3, 128.2, 128.0, 127.8, 127.5, 125.67 (q, J = 3.75
Hz), 125.66, 125.63, 123.87 (q, J = 270.5 Hz), 79.2, 75.3, 74.6, 73.5,
73.3, 69.1, 43.9.
13C NMR (125 MHz, CDCl3):  = 205.0, 148.5, 141.2, 137.5, 136.9,
132.7, 129.7, 128.44, 128.41, 128.2, 128.0, 127.86, 127.80, 123.0,
122.2, 79.0, 75.9, 74.3, 73.6, 73.1, 69.2, 44.1.
HRMS (ESI): m/z [M + H]+ calcd for C26H26NO6: 448.1760; found:
448.1764.
HRMS (ESI): m/z [M + H]+ calcd for C27H26F3O4: 471.1783; found:
471.1784.
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(2-chlorophe-
nyl)dihydro-2H-pyran-4(3H)-one (3an)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

K
A. K. Singh et al.
Paper
Synthesis
Yield: 35 mg (65%); colorless viscous oil; Rf = 0.60 (20% EtOAc/
hexane); []D27 +97 (c 0.1, CHCl3).
(2R,3R,6S)-3-Methoxy-2-(methoxymethyl)-6-(4-nitrophenyl)di-
hydro-2H-pyran-4(3H)-one (3bc)7
IR (neat): 2922, 2790, 1718, 1488, 1120, 745 cm–1
.
The product was purified by column chromatography on silica gel
(25% EtOAc/hexane).
1H NMR (500 MHz, CDCl3):  = 7.44–7.42 (m, 1 H), 7.30–7.15 (m, 13
H), 5.70 (t, J = 6.0 Hz, 1 H), 4.74 (d, J = 11.0 Hz, 1 H), 4.49 (d, J = 12.0
Hz, 1 H), 4.41–4.38 (m, 2 H), 4.14–4.03 (m, 1 H), 3.90–3.87 (m, 1 H),
3.628–3.622 (m, 2 H), 2.93–2.89 (m, 1 H), 2.78 (dd, J = 15.0, 6.5 Hz, 1
H).
13C NMR (125 MHz, CDCl3):  = 206.3, 137.7, 137.3, 137.2, 133.1,
129.8, 129.3, 128.4, 128.3, 128.1, 127.9, 127.69, 127.67, 126.9, 79.2,
75.9, 73.5, 72.9, 71.9, 69.7, 44.6.
26
Yield: 24 mg (64%); white foam; Rf = 0.25 (35% EtOAc/hexane); []D
+104 (c 0.1, CHCl3).
1H NMR (500 MHz, CDCl3):  = 8.14 (d, J = 9.0 Hz, 2 H), 7.51 (d, J = 8.5
Hz, 2 H), 5.43 (t, J = 5.5 Hz, 1 H), 3.87 (d, J = 8.0 Hz, 1 H), 3.62–3.60 (m,
1 H), 3.57–3.56 (m, 2 H), 3.41 (s, 3 H), 3.35 (s, 3 H), 3.02–2.94 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 205.1, 147.6, 146.0, 127.9, 123.8, 81.4,
75.8, 74.4, 71.8, 59.4, 59.2, 43.8.
HRMS (ESI): m/z [M + H]+ calcd for C26H26ClO4: 437.1520; found:
437.1527.
(2R,3S,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-phenyldihy-
dro-2H-pyran-4(3H)-one (3ca)7
(2R,3R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(2,4-dimethyl-
phenyl)dihydro-2H-pyran-4(3H)-one (3ao)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
27
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
Yield: 24 mg (48%); white foam; Rf = 0.62 (20% EtOAc/hexane); []D
+112 (c 0.1, CHCl3).
1H NMR (500 MHz, CDCl3):  = 7.29–7.18 (m, 15 H), 5.25 (dd, J = 10.0,
3.5 Hz, 1 H), 4.86 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 4.5 Hz, 1 H), 4.48 (d,
J = 5.0 Hz, 1 H), 4.42 (d, J = 12.5 Hz, 1 H), 4.38–4.35 (m, 1 H), 4.09 (dd,
J = 6.5, 1.0 Hz, 1 H), 3.78–3.71 (m, 2 H), 2.73 (dd, J = 14.5, 4.0 Hz, 1 H),
2.59–2.54 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 204.1, 140.5, 137.9, 137.4, 128.5,
128.4, 128.3, 128.0, 127.9, 127.8, 127.6, 127.5, 125.9, 79.2, 76.4, 74.7,
73.5, 72.6, 68.4, 47.9.
Yield: 35 mg (65%); colorless viscous oil; Rf = 0.60 (20% EtOAc/hex-
ane); []D27 +59 (c 0.1, CHCl3).
IR (neat): 2820–2977, 1714, 1512, 1118, 1041 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.24–7.18 (m, 10 H), 7.07 (d, J = 8.0 Hz,
1 H), 6.91 (s, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 5.50 (t, J = 5.0 Hz, 1 H), 4.81
(d, J = 11.5 Hz, 1 H), 4.48 (d, J = 12.0 Hz, 1 H), 4.38 (d, J = 11.5 Hz, 2 H),
4.16 (d, J = 8.5 Hz, 1 H), 3.59–3.56 (m, 1 H), 3.53–3.47 (m, 2 H), 2.97–
2.96 (m, 2 H), 2.30 (s, 3 H), 2.19 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 207.5, 138.2, 137.8, 137.5, 137.4,
133.5, 131.9, 128.34, 128.33, 128.1, 127.8, 127.7, 127.6, 127.5, 126.3,
79.7, 73.7, 73.5, 73.4, 72.8, 69.1, 44.3, 20.9, 19.5.
(2R,3S,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-methoxy-
phenyl)dihydro-2H-pyran-4(3H)-one (3cb)8
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
HRMS (ESI): m/z [M + H]+ calcd for C28H31O4: 431.2222; found:
431.2227.
27
Yield: 28 mg (52%); white foam; Rf = 0.45 (20% EtOAc/hexane); []D
= +124 (c 0.1, CHCl3) {Lit.12 []D19 +39.5 (c 0.3, CHCl3)}.
(2R,3R,6S)-3-Methoxy-2-(methoxymethyl)-6-phenyldihydro-2H-
pyran-4(3H)-one (3ba)7
1H NMR (500 MHz, CDCl3):  = 7.31–7.17 (m, 12 H), 6.80 (d, J = 8.5 Hz,
2 H), 5.20 (dd, J = 9.5, 4.0 Hz, 1 H), 4.85 (d, J = 12.0 Hz, 1 H), 4.50–4.49
(m, 2 H), 4.42 (d, J = 12.5 Hz, 1 H), 4.34–4.31 (m, 1 H), 4.07 (dd, J = 6.5,
1.0 Hz, 1 H), 3.77–3.70 (m, 5 H), 2.73 (dd, J = 14.5, 4.0 Hz, 1 H), 2.61–
2.56 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 204.4, 159.4, 137.9, 137.4, 132.5,
128.4, 128.3, 127.9, 127.8, 127.66, 127.60, 127.4, 113.9, 79.3, 76.2,
74.5, 73.5, 72.6, 68.4, 55.3, 47.6.
The product was purified by column chromatography on silica gel
(20% EtOAc/hexane).
27
Yield: 23 mg (72%); white foam; Rf = 0.50 (35% EtOAc/hexane); []D
+53 (c 0.05, CHCl3).
1H NMR (500 MHz, CDCl3):  = 7.31–7.19 (m, 5 H), 5.39 (dd, J = 7.0, 2.5
Hz, 1 H), 3.89 (d, J = 7.5 Hz, 1 H), 3.53–3.51 (m, 3 H), 3.42 (s, 3 H), 3.35
(s, 3 H), 3.05–3.01 (m, 1 H), 2.98–2.93 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 206.5, 138.3, 128.6, 128.1, 127.3, 81.6,
75.1, 74.3, 71.5, 59.4, 59.3, 43.6.
(2R,3S,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-chlorophe-
nyl)dihydro-2H-pyran-4(3H)-one (3cc)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
(2R,3R,6S)-3-Methoxy-2-(methoxymethyl)-6-(4-methoxyphe-
nyl)dihydro-2H-pyran-4(3H)-one (3bb)7
27
Yield: 26 mg (48%); white foam; Rf = 0.64 (20% EtOAc/hexane); []D
The product was purified by column chromatography on silica gel
(20% EtOAc/hexane).
+97 (c 0.1, CHCl3).
IR (neat): 2945, 2861, 1727, 1487, 1128, 734 cm–1
.
27
Yield: 27 mg (76%); white foam; Rf = 0.28 (35% EtOAc/hexane); []D
1H NMR (500 MHz, CDCl3):  = 7.28–7.19 (m, 14 H), 5.22 (dd, J = 10.0,
3.5 Hz, 1 H), 4.87 (d, J = 12.0 Hz, 1 H), 4.51–4.47 (m, 2 H), 4.42 (d, J =
12.5 Hz, 1 H), 4.36–4.33 (m, 1 H), 4.07 (dd, J = 6.5, 1.5 Hz, 1 H), 3.78–
3.70 (m, 2 H), 2.71 (dd, J = 14.5, 3.5 Hz, 1 H), 2.52–2.47 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 203.8, 139.1, 137.8, 137.3, 133.7,
128.7, 128.5, 128.3, 128.0, 127.8, 127.6, 127.3, 79.0, 76.5, 74.1, 73.6,
72.7, 68.4, 47.9.
+167 (c 0.1, CHCl3) {Lit.12 []D17 +128.8 (c 0.4, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 7.21 (d, J = 8.5 Hz, 2 H), 6.78 (d, J = 9.0
Hz, 2 H), 5.34 (dd, J = 6.5, 2.5 Hz, 1 H), 3.87 (d, J = 8.5 Hz, 1 H), 3.71 (s,
3 H), 3.53–3.46 (m, 3 H), 3.43 (s, 3 H), 3.34 (s, 3 H), 2.99 (dd, J = 14.5,
3.0 Hz, 1 H), 2.96–2.92 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 206.7, 159.4, 130.5, 128.8, 114.0, 81.8,
74.8, 73.9, 71.5, 59.5, 59.3, 55.2, 43.8.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

L
A. K. Singh et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C26H26ClO4: 437.1520; found:
13C NMR (125 MHz, CDCl3):  = 206.3, 139.0, 137.2, 128.6, 128.3,
437.1521.
128.1, 128.0, 127.9, 127.0, 84.6, 74.5, 72.9, 71.8, 44.4, 18.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H21O3: 297.1491; found:
297.1497.
(2S,3S,6R)-3-(Benzyloxy)-2-methyl-6-(4-nitrophenyl)dihydro-2H-
pyran-4(3H)-one (3da)7
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
(2R,3R,6S)-3-(Benzyloxy)-6-(4-methoxyphenyl)-2-methyldihydro-
2H-pyran-4(3H)-one (3eb)8
27
Yield: 29 mg (67%); white foam; Rf = 0.25 (20% EtOAc/hexane); []D
–49 (c 0.1, CHCl3).
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
27
1H NMR (500 MHz, CDCl3):  = 8.14–8.11 (m, 2 H), 7.50 (d, J = 8.5 Hz, 2
H), 7.27–7.22 (m, 5 H), 5.24 (t, J = 5.5 Hz, 1 H), 4.73 (d, J = 11.5 Hz, 1
H), 4.40 (d, J = 11.5 Hz, 1 H), 3.81 (quin, J = 6.5 Hz, 1 H), 3.61 (d, J = 7.0
Hz, 1 H), 3.06 (dd, J = 14.5, 5.0 Hz, 1 H), 2.89–2.85 (m, 1 H), 1.24 (d, J =
6.5 Hz, 3 H).
Yield: 30 mg (75%); white foam; Rf = 0.25 (20% EtOAc/hexane); []D
+150 (c 0.1, CHCl3) {Lit.12 []D19 +102.8 (c 0.4, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 7.35–7.28 (m, 7 H), 6.87–6.85 (m, 2 H),
5.27 (dd, J = 6.5, 3.0 Hz, 1 H), 4.87 (d, J = 11.5 Hz, 1 H), 4.49 (d, J = 11.5
Hz, 1 H), 3.82–3.73 (m, 4 H), 3.66 (d, J = 8.0 Hz, 1 H), 3.12 (dd, J = 14.5,
3.0 Hz, 1 H), 2.94 (dd, J = 14.0, 6.5 Hz, 1 H), 1.28 (d, J = 6.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 205.5, 147.5, 146.4, 136.9, 128.4,
128.18, 128.10, 127.7, 123.8, 84.1, 73.6, 73.2, 72.8, 44.4, 17.5.
13C NMR (125 MHz, CDCl3):  = 206.6, 159.2, 137.2, 131.0, 128.6,
128.3, 128.2, 127.9, 113.9, 84.8, 74.3, 73.0, 71.4, 55.2, 44.5, 18.2.
(2S,3S,6R)-3-(Benzyloxy)-2-methyl-6-(3-nitrophenyl)dihydro-2H-
pyran-4(3H)-one (3db)8
(2R,3R,6S)-3-(Benzyloxy)-2-methyl-6-(4-nitrophenyl)dihydro-2H-
pyran-4(3H)-one (3ec)
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
27
Yield: 28 mg (65%); white foam; Rf = 0.25 (20% EtOAc/hexane); []D
–84 (c 0.1, CHCl3) {Lit.12 []D19 –87.3 (c 0.3, CHCl3)}.
27
Yield: 30 mg (70%); white foam; Rf = 0.35 (20% EtOAc/hexane); []D
1H NMR (500 MHz, CDCl3):  = 8.22 (s, 1 H), 8.08–8.07 (m, 1 H), 7.64
(d, J = 7.5 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 7.27–7.22 (m, 5 H), 5.24 (t,
J = 5.5 Hz, 1 H), 4.74 (d, J = 11.5 Hz, 1 H), 4.41 (d, J = 11.5 Hz, 1 H), 3.83
(quin, J = 6.5 Hz, 1 H), 3.62 (d, J = 7.0 Hz, 1 H), 3.09 (dd, J = 14.5, 5.5 Hz,
1 H), 2.88 (dd, J = 14.0, 6.0 Hz, 1 H), 1.25 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 205.5, 148.5, 141.5, 136.9, 132.6,
129.7, 128.4, 128.2, 128.1, 123.0, 122.0, 84.1, 73.5, 73.1, 72.8, 44.5,
17.5.
+87 (c 0.1, CHCl3).
IR (neat): 2949, 2877, 1724, 1531, 1356 cm–1
1H NMR (500 MHz, CDCl3):  = 8.21–8.19 (m, 2 H), 7.57 (d, J = 8.5 Hz, 2
H), 7.36–7.28 (m, 5 H), 5.31 (t, J = 5.5 Hz, 1 H), 4.80 (d, J = 11.5 Hz, 1
H), 4.48 (d, J = 11.5 Hz, 1 H), 3.89 (quin, J = 6.5 Hz, 1 H), 3.70 (dd, J =
7.0, 0.5 Hz, 1 H), 3.13 (dd, J = 14.5, 5.0 Hz, 1 H), 2.96–2.92 (m, 1 H),
1.32 (d, J = 6.5 Hz, 3 H).
.
13C NMR (125 MHz, CDCl3):  = 205.5, 147.5, 146.4, 136.9, 128.4,
128.1, 128.0, 127.7, 123.8, 84.1, 73.6, 73.2, 72.8, 44.5, 17.5.
HRMS (ESI): m/z [M + H]+ calcd for C19H20NO5: 342.1341; found:
342.1344.
(2S,3S,6R)-3-(Benzyloxy)-6-(4-methoxyphenyl)-2-methyldihydro-
2H-pyran-4(3H)-one (3dc)8
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
(2R,3R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-phenyldihy-
dro-2H-pyran-4(3H)-one (3fa)8
27
Yield: 28 mg (68%); white foam; Rf = 0.30 (20% EtOAc/hexane); []D
–64 (c 0.1, CHCl3) {Lit.12 []D27 = –141.2 (c 1.1, CHCl3)}.
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
1H NMR (500 MHz, CDCl3):  = 7.35–7.28 (m, 7 H), 6.86 (d, J = 9.0 Hz, 2
H), 5.27 (dd, J = 7.0, 3.0 Hz, 1 H), 4.87 (d, J = 11.5 Hz, 1 H), 4.49 (d, J =
11.5 Hz, 1 H), 3.82–3.73 (m, 4 H), 3.66 (d, J = 8.0 Hz, 1 H), 3.11 (dd, J =
14.5, 3.0 Hz, 1 H), 2.95–2.91 (m, 1 H), 1.28 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 206.6, 159.2, 137.2, 131.0, 128.6,
128.3, 128.2, 127.9, 113.9, 84.8, 74.3, 73.0, 71.4, 55.2, 44.5, 18.2.
27
Yield: 30 mg (60%); white foam; Rf = 0.63 (20% EtOAc/hexane); []D
+65 (c 0.05, CHCl3) {Lit.12 []D20 +84.8 (c 0.2, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 7.32–7.19 (m, 15 H), 4.86 (d, J = 11.0
Hz, 1 H), 4.61–4.57 (m, 1 H), 4.61 (t, J = 7.2 Hz, 1 H), 4.50 (d, J = 12.5
Hz, 1 H), 4.42 (d, J = 11.5 Hz, 1 H), 4.20–4.18 (m, 1 H), 3.77–3.75 (m, 3
H), 2.69–2.67 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 205.7, 139.9, 138.1, 137.3, 128.5,
128.38, 128.36, 128.2, 128.1, 127.9, 127.69, 127.63, 125.6, 80.8, 79.6,
79.3, 73.5, 69.1, 49.9.
(2R,3R,6S)-3-(Benzyloxy)-2-methyl-6-phenyldihydro-2H-pyran-
4(3H)-one (3ea)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
27
Yield: 27 mg (72%); white foam; Rf = 0.45 (10% EtOAc/hexane); []D
(2R,3R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-methoxy-
phenyl)dihydro-2H-pyran-4(3H)-one (3fb)8
+153 (c 0.1, CHCl3).
IR (neat): 2949, 2877, 1730, 1514, 1166 cm–1
1H NMR (500 MHz, CDCl3):  = 7.39–7.23 (m, 10 H), 5.28 (dd, J = 6.5,
4.0 Hz, 1 H), 4.84 (d, J = 11.5 Hz, 1 H), 4.48 (d, J = 11.5 Hz, 1 H), 3.81
(quin, J = 6.5 Hz, 1 H), 3.66 (d, J = 7.5 Hz, 1 H), 3.14 (dd, J = 14.0, 3.5 Hz,
1 H), 2.93–2.89 (m, 1 H), 1.28 (d, J = 6.5 Hz, 3 H).
.
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
27
Yield: 34 mg (63%); white foam; Rf = 0.42 (20% EtOAc/hexane); []D
+106 (c 0.1, CHCl3) {Lit.12 []D16 +105.0 (c 0.1, CHCl3)}.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

M
A. K. Singh et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3):  = 7.33–7.29 (m, 12 H), 6.89 (d, J = 8.5 Hz,
2 H), 4.93 (d, J = 11.5 Hz, 1 H), 4.65–4.63 (m, 1 H), 4.57 (dd, J = 10.5,
3.0 Hz, 1 H), 4.56 (d, J = 12.5 Hz, 1 H), 4.49 (d, J = 11.0 Hz, 1 H), 4.26 (d,
J = 9.0 Hz, 1 H), 3.82–3.79 (m, 6 H), 2.78–2.69 (m, 2 H).
(2S,3S,6S)-3-(Benzyloxy)-6-(4-methoxyphenyl)-2-methyldihydro-
2H-pyran-4(3H)-one (3ga)8
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
13C NMR (125 MHz, CDCl3):  = 205.9, 159.4, 138.1, 137.4, 132.1,
128.38, 128.35, 128.2, 127.9, 127.7, 127.6, 127.0, 113.9, 80.7, 79.6,
79.1, 73.52, 73.50, 69.1, 55.3, 49.9.
27
Yield: 25 mg (61%); white foam; Rf = 0.35 (20% EtOAc/hexane); []D
–109 (c 0.1, CHCl3) {Lit.12 []D22 –224.9 (c 0.7, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 7.41–7.35 (m, 4 H), 7.32 (d, J = 7.0 Hz, 1
H), 7.28 (d, J = 9.0 Hz, 2 H), 6.90–6.88 (m, 2 H), 4.99 (d, J = 11.5 Hz, 1
H), 4.62 (dd, J = 11.0, 3.0 Hz, 1 H), 4.54 (d, J = 11.5 Hz, 1 H), 3.80 (s, 3
H), 3.77–3.76 (m, 2 H), 2.78–2.68 (m, 2 H), 1.45 (d, J = 5.5 Hz, 3 H).
(2R,3R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-chlorophe-
nyl)dihydro-2H-pyran-4(3H)-one (3fc)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
13C NMR (125 MHz, CDCl3):  = 205.6, 159.4, 137.4, 132.2, 128.4,
128.2, 128.0, 127.0, 114.0, 84.8, 78.9, 77.6, 77.2, 73.2, 55.3, 49.9, 19.3.
27
Yield: 30 mg (55%); white foam; Rf = 0.58 (20% EtOAc/hexane); []D
+53 (c 0.05, CHCl3).
IR (neat): 2949, 2870, 1727, 1514, 1166, 742 cm–1
(2S,3S,6S)-3-(Benzyloxy)-6-(4-nitrophenyl)-2-methyldihydro-2H-
pyran-4(3H)-one (3gb)
.
1H NMR (500 MHz, CDCl3):  = 7.34–7.26 (m, 14 H), 4.93 (d, J = 11.0
Hz, 1 H), 4.66–4.62 (m, 1 H), 4.58 (dd, J = 10.4, 3.2 Hz, 1 H), 4.56 (d, J =
12.5 Hz, 1 H), 4.48 (d, J = 11.0 Hz, 1 H), 4.26–4.24 (m, 1 H), 3.84–3.80
(m, 3 H), 2.74–2.66 (m, 2 H).
The product was purified by column chromatography on silica gel
(20% EtOAc/hexane).
27
Yield: 27 mg (63%); white foam; Rf = 0.30 (20% EtOAc/hexane); []D
–106 (c 0.1, CHCl3).
13C NMR (125 MHz, CDCl3):  = 205.2, 138.5, 138.0, 137.3, 133.8,
128.7, 128.38, 128.35, 128.2, 127.9, 127.6, 127.0, 80.7, 79.5, 78.5,
73.51, 73.50, 69.0, 49.8.
HRMS (ESI): m/z [M + H]+ calcd for C26H26ClO4: 437.1520; found:
437.1525.
IR (neat): 2911, 2821, 1734, 1514, 1358, 841 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.23 (d, J = 9.0 Hz, 2 H), 7.54 (d, J = 8.5
Hz, 2 H), 7.41–7.30 (m, 5 H), 5.99 (d, J = 11.5 Hz, 1 H), 4.78 (dd, J =
12.0, 2.5 Hz, 1 H), 4.55 (d, J = 11.5 Hz, 1 H), 3.85–3.76 (m, 2 H), 2.81–
2.77 (m, 1 H), 2.67–2.61 (m, 1 H), 1.48 (d, J = 5.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 204.2, 147.6, 147.2, 137.2, 128.5,
128.3, 128.1, 126.3, 123.9, 84.5, 77.86, 77.80, 73.4, 49.7, 19.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H20NO5: 342.1341; found:
342.1338.
(2R,3R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(4-bromophe-
nyl)dihydro-2H-pyran-4(3H)-one (3fd)8
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
27
Yield: 38 mg (64%); white foam; Rf = 0.58 (20% EtOAc/hexane); []D
(2R,3R,6S)-3-Hydroxy-2-(hydroxymethyl)-6-phenyldihydro-2H-
pyran-4(3H)-one (4a)
+69 (c 0.1, CHCl3) {Lit.12 []D20 +133.6 (c 0.2, CHCl3)}.
1H NMR (500 MHz, CDCl3):  = 7.42 (d, J = 8.5 Hz, 2 H), 7.26–7.18 (m,
12 H), 4.86 (d, J = 11.0 Hz, 1 H), 4.56–4.55 (m, 1 H), 4.57 (dd, J = 10.5,
3.0 Hz, 1 H), 4.49 (d, J = 12.5 Hz, 1 H), 4.42 (d, J = 11.0 Hz, 1 H), 4.19–
4.17 (m, 1 H), 3.76–3.73 (m, 3 H), 2.68–2.59 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 205.2, 139.0, 138.0, 137.3, 131.7,
128.4, 128.3, 128.2, 128.0, 127.7, 127.3, 122.0, 80.7, 79.5, 78.6, 73.55,
73.53, 69.0, 49.8.
To a solution of 3ab (100 mg, 0.25 mmol) in methanol/EtOAc/AcOH
(1:1:.2) was added 10% Pd/C (25 mg) and the resulting suspension
was stirred for 24 h at room temperature in the presence of H2 gas
(balloon). The Pd/C was removed from the reaction by filtration
through Celite and the filtrate was concentrated. The crude product
was purified by silica gel column chromatography (hexane/ethyl ace-
tate, 50:50) to afford the pure product 4a.
Yield: 52 mg (92%); colorless oil; []D26 = +57 (c 0.1, CHCl3).
(2R,3R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-(p-tolyl)dihy-
dro-2H-pyran-4(3H)-one (3fe)
IR (neat): 3353, 1721, 831 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.32–7.21 (m, 5 H), 5.48 (d, J = 7.5 Hz, 1
H), 4.25 (d, J = 10.0 Hz, 1 H), 3.79–3.72 (m, 2 H), 3.57 (s, 1 H), 3.27–
3.23 (m, 1 H), 3.17–3.14 (m, 1 H), 3.10–3.06 (m, 1 H), 2.24 (s, 1 H).
13C NMR (125 MHz, CDCl3):  = 207.8, 137.8, 128.8, 128.3, 127.4, 76.2,
75.4, 73.6, 62.5, 41.6.
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
27
Yield: 35 mg (68%); white foam; Rf = 0.62 (20% EtOAc/hexane); []D
+74 (c 0.1, CHCl3).
IR (neat): 2952, 2894, 1729, 1515, 1248, 833 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C12H15O4: 223.0970; found:
223.0957.
1H NMR (500 MHz, CDCl3):  = 7.40–7.39 (m, 1 H), 7.36–7.30 (m, 11
H), 7.20 (d, J = 8.0 Hz, 2 H), 4.96 (d, J = 11.0 Hz, 1 H), 4.72–4.67 (m, 1
H), 4.67 (dd, J = 10.8, 2.9 Hz, 1 H), 4.59 (d, J = 12.5 Hz, 1 H), 4.52 (d, J =
11.0 Hz, 1 H), 4.30 (d, J = 9.0 Hz, 1 H), 3.86–3.83 (m, 3 H), 2.82–2.73
(m, 2 H), 2.37 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 205.9, 138.1, 137.9, 137.4, 137.0,
129.2, 128.5, 128.38, 128.35, 128.2, 127.9, 127.7, 127.6, 126.9, 125.6,
80.8, 79.6, 79.3, 73.51, 73.50, 69.1, 49.9, 21.1.
(2R,3S,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-4-methylene-6-
phenyltetrahydro-2H-pyran (4b)
A solution of n-BuLi (0.6 mL, 1.6 M in n-hexane, 1.0 mmol) was added
to a stirred suspension of methyltriphenylphosphonium bromide
(355 mg, 1.0 mmol) in dry THF (10 mL) at –20 °C. The reaction mix-
ture was stirred at the same temperature for 1 h and then treated
with a solution of compound 3ab (200 mg, 0.5 mmol) in dry THF (5
mL). Following the addition, the mixture was allowed to stir at room
temperature for 5 h. After completion, the reaction mixture was
HRMS (ESI): m/z [M + H]+ calcd for C27H29O4: 417.2066; found:
417.2061.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

N
A. K. Singh et al.
Paper
Synthesis
poured into ice water and then extracted with CH2Cl2. The organic
layer was washed with brine, dried over anhydrous Na2SO4 and evap-
orated. The crude residue was purified by silica gel column chroma-
tography (hexane/ethyl acetate, 90:10) to afford the pure alkene 4b.
(d, J = 3.5 Hz, 2 H), 3.60 (d, J = 8.5 Hz, 1 H), 2.45 (dd, J = 14.5, 3.5 Hz, 1
H), 2.06 (dd, J = 14.5, 6.5 Hz, 1 H), 1.65–1.59 (m, 1 H), 1.51–1.43 (m, 2
H), 1.35–1.24 (m, 5 H), 0.90 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 141.5, 137.9, 137.8, 128.9, 128.5,
128.4, 128.35, 128.32, 128.0, 127.7, 127.67, 127.64, 126.6, 126.0, 77.8,
74.4, 73.5, 72.4, 72.3, 70.2, 69.6, 40.0, 35.9, 32.4, 22.9, 22.6, 14.0.
Yield: 155 mg (78%); colorless viscous oil; []D27 +17 (c 0.1, CHCl3).
IR (neat): 2842, 1615, 1248, 814 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C31H39O4: 475.2848; found:
475.2845.
1H NMR (500 MHz, CDCl3):  = 7.33 (d, J = 7.5 Hz, 2 H), 7.25–7.15 (m,
13 H), 5.03 (s, 1 H), 4.91 (s, 1 H), 4.59 (dd, J = 9.5, 3.5 Hz, 1 H), 4.54 (d,
J = 11.5 Hz, 1 H), 4.44 (s, 2 H), 4.30 (d, J = 12.0 Hz, 1 H), 4.17–4.14 (m,
1 H), 3.80 (d, J = 3.0 Hz, 1 H), 3.60 (dd, J = 10.0, 6.0 Hz, 1 H), 3.53 (dd,
J = 10.0, 7.0 Hz, 1 H), 2.67 (dd, J = 13.5, 10.0 Hz, 1 H), 2.33 (dd, J = 13.5,
3.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 141.5, 141.0, 138.2, 138.0, 128.32,
128.30, 128.2, 127.7, 127.67, 127.60, 127.4, 126.2, 113.8, 76.8, 76.1,
74.4, 73.0, 70.0, 67.7, 37.9.
(2R,3R,4R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-4-isopropyl-
6-phenyltetrahydro-2H-pyran-4-ol (4e)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
Yield: 77 mg (70%); colorless viscous oil; Rf = 0.68 (20% EtOAc/hex-
ane); []D26 +17 (c 0.05, CHCl3).
HRMS (ESI): m/z [M + H]+ calcd for C27H29O3: 401.2117; found:
IR (neat): 3311, 2886, 1522, 1212, 836 cm–1
.
401.2113.
1H NMR (500 MHz, CDCl3):  = 7.48–7.46 (m, 2 H), 7.39–7.26 (m, 10
H), 7.23–7.21 (m, 1 H), 7.14 (dd, J = 7.5, 2.0 Hz, 2 H), 5.09 (dd, J = 6.5,
3.5 Hz, 1 H), 4.71 (d, J = 12.0 Hz, 1 H), 4.57–4.54 (m, 3 H), 3.93–3.87
(m, 2 H), 3.78–3.72 (m, 2 H), 2.34 (dd, J = 14.5, 3.5 Hz, 1 H), 2.10–2.04
(m, 1 H), 2.00–1.94 (m, 1 H), 1.04 (d, J = 7.0 Hz, 3 H), 1.01 (d, J = 7.0 Hz,
3 H).
13C NMR (125 MHz, CDCl3):  = 141.7, 138.0, 137.9, 128.37, 128.33,
128.0, 127.9, 127.7, 127.6, 127.4, 126.5, 126.1, 77.2, 74.9, 74.8, 74.0,
73.6, 72.4, 70.1, 69.8, 34.0, 18.1, 16.2.
Grignard Reaction; General Procedure
To a stirred solution of compound 3ab (100 mg, 0.25 mmol) in dry
THF (10 mL) at –20 °C was added dropwise a solution of the corre-
sponding Grignard reagent (RMgBr) in THF or Et2O (0.35 mmol) via a
syringe. The resulting mixture was stirred at this temperature for 30
min and then at room temperature for another 2–3 h. After comple-
tion, the reaction mixture was diluted with ice-cold water and ex-
tracted with CH2Cl2. The organic layer was washed with brine, dried
over anhydrous Na2SO4 and evaporated in vacuo. The residue was pu-
rified by silica gel column chromatography (hexane/ethyl acetate) to
afford the product 4c–h.
HRMS (ESI): m/z [M + H]+ calcd for C29H35O4: 447.2535; found:
447.2531.
(2R,3R,4R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-phenyl-4-
vinyltetrahydro-2H-pyran-4-ol (4f)
(2R,3R,4S,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-4-methyl-6-
phenyltetrahydro-2H-pyran-4-ol (4c)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
The product was purified by column chromatography on silica gel
(15% EtOAc/hexane).
Yield: 80 mg (75%); yellowish viscous oil; Rf = 0.65 (20% EtOAc/hex-
ane); []D26 +59 (c 0.1, CHCl3).
Yield: 89 mg (86%); yellowish viscous oil; Rf = 0.70 (20% EtOAc/hex-
ane); []D26 +26 (c 0.1, CHCl3).
IR (neat): 3261, 2869, 1519, 1248, 825 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.49–7.48 (m, 2 H), 7.38–7.24 (m, 10
H), 7.21–7.20 (m, 1 H), 7.10–7.09 (m, 2 H), 5.98 (dd, J = 17.0, 10.5 Hz, 1
H), 5.46 (d, J = 17.0 Hz, 1 H), 5.20 (d, J = 10.5 Hz, 1 H), 5.09 (d, J = 5.5
Hz, 1 H), 4.69 (d, J = 12.0 Hz, 1 H), 4.55 (dd, J = 10.5, 3.5 Hz, 2 H), 4.44
(d, J = 10.5 Hz, 1 H), 3.92–3.89 (m, 1 H), 3.74 (d, J = 3.5 Hz, 2 H), 3.70
(d, J = 9.0 Hz, 1 H), 2.49 (dd, J = 14.5, 2.0 Hz, 1 H), 2.24 (dd, J = 15.0, 7.0
Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 143.4, 140.9, 138.0, 137.6, 128.5,
128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.74, 127.67, 127.64, 126.5,
126.2, 125.9, 114.4, 77.4, 74.4, 73.6, 72.7, 72.0, 69.3, 69.2, 36.6.
IR (neat): 3460, 2914, 2894, 1515, 1248, 798 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.39 (d, J = 7.5 Hz, 2 H), 7.31–7.11 (m,
13 H), 4.94 (dd, J = 6.0, 4.0 Hz, 1 H), 4.61 (d, J = 12.0 Hz, 1 H), 4.54–4.47
(m, 3 H), 3.88–3.85 (m, 1 H), 3.68 (d, J = 3.5 Hz, 2 H), 3.48 (d, J = 8.0 Hz,
1 H), 2.43 (dd, J = 14.5, 3.5 Hz, 1 H), 2.01 (dd, J = 14.5, 6.5 Hz, 2 H), 1.23
(s, 3 H).
13C NMR (125 MHz, CDCl3):  = 141.2, 137.9, 137.7, 128.36, 128.33,
128.02, 128.01, 127.77, 127.70, 127.6, 126.6, 126.0, 79.0, 74.5, 73.5,
72.3, 70.28, 70.24, 69.3, 38.8, 27.6.
HRMS (ESI): m/z [M + H]+ calcd for C27H31O4: 419.2222; found:
419.2217.
HRMS (ESI): m/z [M + H]+ calcd for C28H31O4: 431.2222; found:
431.2228.
(2R,3R,4S,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-4-pentyl-6-
phenyltetrahydro-2H-pyran-4-ol (4d)
(2R,3R,4R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-phenyl-4-
(p-tolyl)tetrahydro-2H-pyran-4-ol (4g)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
Yield: 94 mg (80%); yellowish viscous oil; Rf = 0.70 (20% EtOAc/hex-
ane); []D26 +26 (c 0.1, CHCl3).
Yield: 86 mg (70%); colorless viscous oil; Rf = 0.70 (20% EtOAc/hex-
ane); []D26 +27 (c 0.1, CHCl3).
IR (neat): 3252, 2894, 1500, 1244, 811 cm–1
.
IR (neat): 3221, 2886, 1511, 1236, 789 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.47–7.45 (m, 2 H), 7.39–7.36 (m, 2 H),
7.34–7.26 (m, 8 H), 7.22–7.16 (m, 3 H), 5.03 (dd, J = 6.0, 4.5 Hz, 1 H),
4.69 (d, J = 12.0 Hz, 1 H), 4.59–4.53 (m, 3 H), 4.94–3.92 (m, 1 H), 3.75
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P

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A. K. Singh et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3):  = 7.53–7.47 (m, 4 H), 7.39–7.37 (m, 2 H),
7.35–7.27 (m, 6 H), 7.20–7.12 (m, 5 H), 6.77 (dd, J = 7.5, 1.5 Hz, 2 H),
5.21 (d, J = 6.5 Hz, 1 H), 4.71 (d, J = 12.0 Hz, 1 H), 4.55 (d, J = 12.0 Hz, 1
H), 4.11–4.06 (m, 2 H), 3.99–3.96 (m, 1 H), 3.75–3.72 (m, 4 H), 2.71–
2.68 (m, 1 H), 2.58 (dd, J = 15.5, 7.5 Hz, 1 H), 2.36 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 143.3, 141.0, 138.0, 137.4, 136.6,
128.9, 128.3, 128.06, 128.05, 127.9, 127.7, 127.6, 127.5, 126.4, 126.2,
125.2, 78.8, 74.2, 74.1, 73.6, 72.5, 69.5, 69.4, 67.9, 39.2, 20.9.
Vlahov, I. R. Tetrahedron 1998, 54, 9913. (d) Kitamura, K.; Ando,
Y.; Matsumoto, T.; Suzuki, K. Chem. Rev. 2018, 118, 1495.
(e) Yang, Y.; Yu, B. Chem. Rev. 2017, 117, 12281. (f) Bililign, T.;
Griffith, B. R.; Thorson, J. S. Nat. Prod. Rep. 2005, 22, 742.
(g) Koester, D. C.; Leibeling, M.; Neufeld, R.; Werz, D. B. Org. Lett.
2010, 12, 3934. (h) Koester, D. C.; Werz, D. B. Beilstein J. Org.
Chem. 2012, 8, 675. (i) Koester, D. C.; Kriemen, E.; Werz, D. B.
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H. Helv Chim. Acta 1987, 70, 1217.
HRMS (ESI): m/z [M + H]+ calcd for C33H35O4: 495.2535; found:
495.2539.
(3) (a) Kaelin, D. E.; Lopez, O. D.; Martin, S. F. J. Am. Chem. Soc. 2001,
123, 6937. (b) Zhu, F.; Rodriguez, J.; Yang, T.; Kevlishvili, I.;
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Zhang, L. H.; Ye, X. S. Org. Lett. 2009, 11, 1709. (d) Bai, Y. G.; Kim,
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Legros, F.; Guillarme, S.; Martel, A.; Lebreton, J.; Carreaux, F.;
Dujardin, G.; Collet, S. Chem. Eur. J. 2018, 24, 14069.
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2006, 106, 4622. (b) Mo, F. Y.; Dong, G. B.; Zhang, Y.; Wang, J. B.
Org. Biomol. Chem. 2013, 11, 1582. (c) Colleville, A. P.; Horan, R.
A. J.; Olazabal, S.; Tomkinson, N. C. O. Org. Process Res. Dev.
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Lewis, N. Chem. Commun. 1996, 737. (e) Beletskaya, I. P.; Sigeev,
A. S.; Peregudov, A. S.; Petrovskii, P. V. Synthesis 2007, 2534.
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J. J. Organomet Chem. 2005, 690, 3822. (b) Zhilong, L.; Leung, T.
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(d) Meira, P. R. R.; Moro, A. V.; Correia, C. R. D. Synthesis 2007,
2279. (e) Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia,
C. R. D. Org. Lett. 2003, 5, 305. (f) Oliveira, D. F.; Severino, E. A.;
Correia, C. R. D. Tetrahedron. Lett. 1999, 40, 2083. (g) Machado,
A. H. L.; de Sousa, M. A.; Patto, D. C. S.; Azevedo, L. F. S.;
Bombonato, F. I.; Correia, C. R. D. Tetrahedron Lett. 2009, 50,
1222. (h) Siqueira, F. A.; Taylor, J. G.; Correia, C. R. D. Tetrahedron
Lett. 2010, 51, 2102. (i) Prediger, P.; da Silva, A. R.; Correia, C. R.
D. Tetrahedron 2014, 70, 3333. (j) Schmidt, B.; Holter, F.; Kelling,
A.; Schilde, U. J. Org. Chem. 2011, 76, 3357. (k) Schmidt, B.;
Holter, F. A. Chem. Eur. J. 2009, 15, 11948. (l) Schmidt, B.;
Biernat, A. Eur. J. Org. Chem. 2008, 5764. (m) Schmidt, B. Chem.
Commun. 2003, 1656. (n) Schmidt, B. A. Org. Lett. 2000, 2, 791.
(7) Singh, A. K.; Kandasamy, J. Org. Biomol. Chem. 2018, 16, 5107.
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2018, 20, 3079.
(2R,3R,4R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-4,6-diphen-
yltetrahydro-2H-pyran-4-ol (4h)
The product was purified by column chromatography on silica gel
(10% EtOAc/hexane).
Yield: 91 mg (76%); colorless viscous oil; Rf = 0.68 (20% EtOAc/hex-
ane); []D26 +29 (c 0.1, CHCl3).
IR (neat): 3251, 2785, 1541, 833 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.62–7.60 (m, 2 H), 7.54–7.52 (m, 2 H),
7.40–7.21 (m, 11 H), 7.15–7.10 (m, 3 H), 6.74–6.72 (m, 2 H), 5.22 (d,
J = 6.5 Hz, 1 H), 4.71 (d, J = 12.5 Hz, 1 H), 4.56 (d, J = 12.5 Hz, 1 H), 4.12
(d, J = 9.5 Hz, 1 H), 4.07 (d, J = 10.5 Hz, 1 H), 4.00–3.97 (m, 1 H), 3.78–
3.73 (m, 2 H), 3.68 (d, J = 10.5 Hz, 1 H), 2.72 (dd, J = 15.0, 1.5 Hz, 1 H),
2.60 (dd, J = 15.0, 6.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 146.2, 140.9, 138.0, 137.3, 128.3,
128.2, 128.08, 128.06, 127.9, 127.66, 127.59, 127.5, 127.0, 126.4,
126.1, 125.3, 78.8, 77.2, 74.3, 74.2, 73.6, 72.5, 69.5, 69.4, 39.1.
HRMS (ESI): m/z [M + H]+ calcd for C32H33O4: 481.2379; found:
481.2384.
Funding Information
J.K. acknowledges the Department of Science and Technology, India
(DST-India) (DST/INT/MPG/P-09/2016) and the Max-Planck Society,
Germany for financial support through an Indo-Max Planck partner
group project. A.K.S. acknowledges the Council of Scientific and In-
dustrial Research (CSIR) for a senior research fellowship [File No:
09/1217(0005/2015-EMR-I]. R.V. is grateful to the Indian Institute of
Technology (IIT) (BHU) for a research fellowship. (C)
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Acknowledgment
We thank Dr. M. S. Muthu, IIT (BHU) for HPLC studies and Dr. S. Krish-
namurthy, IIT (BHU) for NMR studies. J.K. acknowledges the NMR fa-
cilities of the Central Instrumentation Facility Center (CIFC), IIT
(BHU).
Supporting Information
(9) (a) Li, P. F.; Jia, X. D. Synthesis 2018, 50, 711. (b) Csende, F. Mini-
Rev. Org. Chem. 2015, 12, 127. (c) He, L. M.; Qiu, G. Y. S.; Gao, Y.
Q.; Wu, J. Org. Biomol. Chem. 2014, 12, 6965. (d) Oger, N.;
d’Halluin, M.; Le Grognec, E. L.; Felpin, F. X. Org. Process Res. Dev.
2014, 18, 1786.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611916.
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References
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–P